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Background: The combination of CDK4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) is currently the standard first-line treatment for patients with metastatic hormone receptor positive (HR+), and HER2-negative (HER2-) breast cancer. However, the impact of HER2 status on the prognosis of patients receiving CDK4/6i and ET remains unclear. The meta-analysis was conducted to evaluate different outcomes between HER2-low and HER2-zero patients in advanced HR+ breast cancer receiving CDK4/6i and ET. Methods: A systematic search was performed in PubMed and EMBASE databases for relevant published literature. Objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) were pooled by fixed or random effects models. Results: Overall, 12 studies with 3567 patients were eligible for analysis. The pooled analysis suggested that no significant differences were observed in terms of ORR and OS between HER2-low and HER2-zero patients who underwent CDK4/6i and ET. Similarly, no significant difference in PFS was found between HER2-low and HER2-zero patients who underwent post-line CDK4/6i and ET or first-line Palbociclib and ET. However, in patients who received mixed-line (not a single treatment line) or first-line CDK4/6i and ET, the PFS was significantly shorter in the HER2-low subgroup than in the HER2-zero subgroup (mixed-line: HR = 1.36; 95% CI = 1.11–1.65; P = 0.002; first-line: HR = 1.14; 95% CI = 1.01– 1.28; P = 0.04). A similar phenomenon was observed in patients who received mixed-line or post-line Palbociclib and ET (mixed-line: HR = 1.60; 95% CI = 1.09–2.34; P = 0.02; post-line: HR = 1.43; 95% CI = 1.03–2.00; P = 0.03). Conclusion: These results indicated that HER2-low status did not have a significant association with ORR and OS, but it may have a worse impact on PFS in patients who received mixed-line or first-line CDK4/6i and ET, as well as mixed-line or post-line palbociclib plus ET. [ABSTRACT FROM AUTHOR]

Introduction: CDK4/6 inhibitors are the first-line treatment for HR+/HER2- advanced breast cancer. Despite their clinical benefit, they can increase healthcare expenditure. To date, there is no thorough comparison among the three approved CDK4/6 inhibitors in terms of their cost-effectiveness. Objective: To investigate and compare the cost-effectiveness of CDK4/6 inhibitors in combination with letrozole as a first-line treatment for advanced breast cancer with hormonal-receptor-positivity and HER-2-negativity versus one another and versus letrozole monotherapy. Methods: A 10-year within-cycle-corrected Markov’s model was employed from the healthcare payer perspective. Costs were obtained from the National Center for Cancer Care and Research (NCCCR) in Qatar. Utilities and transition probabilities were calculated from published landmark trials of PALOMA-2, MONALEESA-2, MONARCH-3, PO25, and other relevant literature. Costs, measured in Qatari Riyal (QAR), and effectiveness, measured in qualityadjusted-life-years (QALYs), were incremented and the incremental costeffectiveness ratio (ICER) was compared to a willingness-to-pay threshold (WTP) of 1.5 Qatari GDP (448,758 QAR). A deterministic sensitivity analysis was implemented to account for uncertainties. Results: Ribociclib was the most effective option, generating 4.420 QALYs, followed by palbociclib (4.406 QALYs), abemaciclib (4.220 QALYs), then letrozole monotherapy (2.093 QALYs). As for cost-effectiveness, ribociclib dominated palbociclib. However, it was not cost-effective compared to abemaciclib (ICER=1,588,545 QAR/QALY). Ribociclib remained dominant over palbociclib with all uncertainties. The base-case conclusion of ribociclib versus abemaciclib remained robust over all uncertainties. Conclusion: From the healthcare payer perspective in Qatar, ribociclib is the most effective CDK4/6 inhibitor. It was dominant over palbociclib in terms of cost-effectiveness; however, it was not cost-effective compared to abemaciclib at current prices. [ABSTRACT FROM AUTHOR]

Introduction: Diffuse pleural mesothelioma (DPM) of the pleura is a highly aggressive and treatment-resistant cancer linked to asbestos exposure. Despite multimodal treatment, the prognosis for DPM patients remains very poor, with an average survival of 2 years from diagnosis. Cisplatin, a platinum-based chemotherapy drug, is commonly used in the treatment of DPM. However, the development of resistance to cisplatin significantly limits its effectiveness, highlighting the urgent need for alternative therapeutic strategies. New selective inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) have shown promise in various malignancies by inhibiting cell cycle progression and suppressing tumor growth. Recent studies have indicated the potential of abemaciclib for DPM therapy, and a phase II clinical trial has shown preliminary encouraging results. Methods: Here, we tested abemaciclib, palbociclib, and ribociclib on a panel of DPM cell lines and non-tumor mesothelial(MET-5A) cells. Results: Specifically, we focused on abemaciclib, which was the mosteffective cytotoxic agent on all the DPM cell lines tested. Abemaciclib reduced DPM cell viability, clonogenic potential, and ability to grow as three-dimensional (3D) spheroids. In addition, abemaciclib induced prolonged effects, thereby impairing second-generation sphere formation and inducing G0/G1 arrest and apoptosis/necrosis. Interestingly, single silencing of RB family members did not impair cell response to abemaciclib, suggesting that they likely complement each other in triggering abemaciclib's cytostatic effect. Interestingly, abemaciclib reduced the phosphorylation of AKT, which is hyperactive in DPM and synergized with the pharmacological AKT inhibitor (AKTi VIII). Abemaciclib also synergized with cisplatin and reduced the viability of DPM cells with acquired resistance to cisplatin. Discussion: Overall, our results suggest that CDK4/6 inhibitors alone or in combination with standard of care should be further explored for DPM therapy. [ABSTRACT FROM AUTHOR]

Background: Since the European approval of CDK4/6 inhibitors in 2016, the treatment of patients with hormone-receptor-positive, HER2-negative metastatic breast cancer has changed significantly. Compared with chemotherapy, endocrine-based therapy has different treatment regimens and is associated with new side effects. Oral therapy aims for optimal drug efficacy and long treatment times while maintaining maximum independence and quality of life resulting in the conservation of medical staff resources. Methods: A monocentric analysis of therapy preferences of practitioners (25 nurses and physicians) and patients (11 on endocrine monotherapy, 17 on endocrine-based therapy, and 14 on intravenous chemotherapy) was performed using specific questionnaires. Preferences were assessed using a four-point Likert scale or bidirectional response options. Results: All patients were highly supportive of oral therapy (mean agreement score on the Likert scale 1.3, p < 0.001 vs. all other options) and a consultation interval of 4 weeks (2.0, p = 0.015 vs. 3 weeks). Practitioners also preferred oral therapy (1.4) and visits every 4 weeks (1.6). In general, patients on oral therapies reported higher compatibility of their therapy with daily life than patients on chemotherapy (1.6 and 1.7 vs. 2.6, p = 0.006). Outpatient oncology is the main source of information for all patients, mainly in case of side effects (2.0) and open questions (1.8). Regarding oral antitumor therapy regimens, patients do not show a significant preference for a specific regimen, while practitioners prefer a continuous regimen (1.6) over a 21/7 regimen (21 days on and 7 days off therapy, 2.5). Patients are likely to accept mild side effects (e.g., neutropenia, diarrhea, polyneuropathy, fatigue) and would still adhere to their initial choice of regimen (continuous or 21/7). Only when side effects occur with a severity of CTCAE grade 3 do patients prefer the regimen in which the side effects occur for a shorter period of time. Conclusion: Patients and practitioners prefer oral antitumor therapy—both continuous and 21/7 regimens—over other application forms. Patient education and proper therapy management, supported by additional tools, contribute to the specific management of side effects and high adherence. This allows quality of life to be maintained during long-term therapy with CDK4/6 inhibitors in patients with metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) represent the gold standard of the hormone receptor positive human epidermal growth factor receptor 2 (HER-2) negative advanced breast cancer. However, optimal treatment after disease progression is a matter of debate. We aimed to assess predictive and prognostic factors associated with the treatment outcome following CDK4/6i progression. Methods: We retrospectively analyzed patients who progressed on CDK4/6i treatment between 2018 and 2024. Treatment based on molecular findings (PIK3CA mutation), genetic findings (BRCA1/2 germline mutation), or adapted to the change in the tumor phenotype in rebiopsy (anti-HER2 therapy in the transformation to HER-2-positive disease) was grouped into tailored treatment and compared to the endocrine-based therapy and chemotherapy alone. Results: Five hundred twelve patients were treated with CDK4/6i. Two hundred patients with disease progression were enrolled in the study. Duration of response to CDK4/6i was not predictive of the response to subsequent treatment, whereas the progression in the central nervous system was the worst prognostic factor. Thirty patients were ineligible for subsequent treatment. Survival after CDK4/6i progression was significantly longer in patients eligible for tailored treatment. The median PFS in patients with tailored treatment (n=19) was 13.5 months vs. 4.9 months in patients with non-tailored therapy (n=151; p=0.045). 12-month PFS was 54.1% with tailored treatment [95% CI 24.1–76.7%] compared to 18.5% with non-tailored therapy [95% CI 11.6– 26.6%]. The median OS for patients treated with a tailored approach was not reached compared to 11.5 months with non-tailored treatment (p=0.016). The 24-month OS for patients treated with a tailored approach was 80.2% [95% CI 40.3–94.8%] compared to 21.1% [95% CI 12.2–31.7%] for patients with nontailored treatment. Conclusions: Tailoring of subsequent treatment strategy seems to be essential for achieving long-term benefit. Further studies are required, as the prognosis after CDK4/6i progression remains dismal, especially in cases affecting the central nervous system. [ABSTRACT FROM AUTHOR]

Background: Osteosarcoma is a leading subtype of bone tumor affecting adolescents and adults. Comparative molecular characterization among different age groups, especially in pediatric, adolescents and adults, is scarce. Methods: We collected samples from 194 osteosarcoma patients, encompassing pediatric, adolescent, and adult cohorts. Genomic analyses were conducted to reveal prevalent mutations and compare molecular features in pediatric, adolescent, and adult patients. Results: Samples from 194 osteosarcoma patients across pediatric to adult ages were analyzed, revealing key mutations such as TP53, FLCN, NCOR1, and others. Children and adolescents showed more gene amplifications and HRD mutations, while adults had a greater Tumor Mutational Burden (TMB). Mutations in those over 15 were mainly in cell cycle and PI3K/mTOR pathways, while under 15s had more in cell cycle and angiogenesis with higher VEGFA, CCND3, TFEB mutations. CNV patterns varied with age: VEGFA and XPO5 amplifications more in under 25s, and CDKN2A/B deletions in over 25s. Genetic alterations in genes like MCL1 and MYC were associated with poor prognosis, with VEGFA mutations also indicating worse outcomes. 58% of patients had actionable mutations, suggesting opportunities for targeted therapies. Age-specific patterns were observed, with Multi-TKI mutations more common in younger patients and CDK4/6 inhibitor mutations in adults, highlighting the need for personalized treatment approaches in osteosarcoma. In a small group of patients with VEGFR amplification, postoperative treatment with multi-kinase inhibitors resulted in a PR in 3 of 13 cases, especially in patients under 15. A significant case involved a 13-year-old with a notable tumor size reduction achieving PR, even with other genetic alterations present in some patients with PD. Conclusion: This study delineates the molecular differences among pediatric, adolescent, and adult osteosarcoma patients at the genomic level, emphasizing the necessity for precision diagnostics and treatment strategies, and may offer novel prognostic biomarkers for patients with osteosarcoma. These findings provide a significant scientific foundation for the development of individualized treatment approaches tailored to patients of different age groups. [ABSTRACT FROM AUTHOR]

Background: Remimazolam is a new ultrashort-acting benzodiazepine for sedation and anesthesia. The effects of remimazolam and the mechanism by which it functions in cancer cells have not been determined. This research aimed to explore the mechanism of remimazolam action in colon cancer treatment, using bioinformatics analysis and in vitro experiments. Methods: Cell cycle progression, colony formation, self-renewal capacity, and apoptosis detection were performed in HCT8 cells treated with or without remimazolam. Transcriptome sequencing, Gene Ontology, Kyoto Encyclopedia of Genes and Genome, Protein-Protein Interaction, Gene Set Enrichment Analysis, Western blotting, and qPCR were performed to investigate the mechanism of action of remimazolam in HCT8 colon cancer cells. Results: Remimazolam promoted proliferation and cell-cycle progression of HCT8 cells. After remimazolam treatment, a total of 1,096 differentially expressed genes (DEGs) were identified: 673 genes were downregulated, and 423 genes were upregulated. The DEGs were enriched mainly in "DNA replication", "cell cycle", and "G1/S transition" related pathways. There were 15 DEGs verified by qPCR, and representative biomarkers were detected by Western Bloting. The remimazolam-mediated promotion of cell proliferation and cell cycle was reversed by G1T28, a CDK4/6 inhibitor. Conclusion: Remimazolam promoted cell-cycle progression and proliferation in HCT8 colon cancer cells, indicating that the long-term use of remimazolam has potential adverse effects in the anesthesia of patients with colon cancer. [ABSTRACT FROM AUTHOR]

Locally advanced breast cancer poses significant challenges to the multidisciplinary team, in particular with hormone receptor (HR) positive, HER2- negative tumors that classically yield lower pathological complete responses with chemotherapy. The increasingly significant use of CDK 4/6 inhibitors (CDK4/6i) plus endocrine therapy (ET) in different breast cancer settings has led to clinical trials focusing on this strategy as a primary treatment, with promising results. The impact of the microbiota on cancer, and vice-versa, is an emerging topic in oncology. The authors report a clinical case of a postmenopausal female patient with an invasive breast carcinoma of the right breast, Luminal B-like, staged as cT4cN3M0 (IIIB). Since the lesion was considered primarily inoperable, the patient started letrozole and ribociclib. Following 6 months of systemic therapy, the clinical response was significant, and surgery with curative intent was performed. The final staging was ypT3ypN2aM0, R1, and the patient started adjuvant letrozole and radiotherapy. This case provides important insights on primary CDK4/6i plus ET in locally advanced unresectable HR+/HER2- breast cancer and its potential implications in disease management further ahead. The patient's gut microbiota was analyzed throughout the disease course and therapeutic approach, evidencing a shift in gut microbial dominance from Firmicutes to Bacteroidetes and a loss of microbial diversity following 6 months of systemic therapy. The analysis of the intratumoral microbiota from the surgical specimen revealed high microbial dissimilarity between the residual tumor and respective margins. [ABSTRACT FROM AUTHOR]

Background: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver malignancy with a steadily increasing incidence worldwide. ICC has insidious onset, rapid progression, and poor prognosis. More multidisciplinary clinical studies are needed to continuously explore safer and more efficient diagnosis and treatment modes for ICC. Methods and results: A 66-year-old female patient with ICC rapidly developed systemic multiple metastases after surgery, and the first-line two-drug combination chemotherapy was not effective. Due to cyclin-dependent kinase inhibitor 2A mutation and programmed cell death-ligand 1-positive, a partial response and progression-free survival of 9.5 months were achieved after a second-line treatment with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) combined with immunotherapy. The patient developed thromboembolism 7 months after treatment and died due to disseminated intravascular coagulation. Conclusion: The combination of targeted and immune therapy has revealed a potentially effective regimen for the effective treatment of patients with ICC, which needs to be observed in larger clinical studies. The thromboembolism rates in real-world patients treated with CDK4/6 inhibitors are higher than those reported in clinical trials, and the application of prophylactic anticoagulation in this patient population may be questionable. [ABSTRACT FROM AUTHOR]

Breast cancer is a significant global health concern, contributing to substantial morbidity and mortality among women. Hormone receptor-positive (HR+)/HER2- negative (HER2-) breast cancer constitutes a considerable proportion of cases, and significant advancements have been made in its management. CDK4/6 inhibitors (CDK4/6is) are a new targeted therapy that has demonstrated efficacy in adjuvant, advanced and metastatic settings. The propensity of lobular breast carcinomas for estrogen-rich sites, such as periocular tissues and orbital fat, may explain their tendency for orbital metastases. Current treatment strategies for these cases are predominantly palliative, and the prognosis remains poor. This article presents a unique case of a 51-year-old female with progressive right periorbital edema, pain, and limited ocular motility. An imaging work-up showed bilateral intra and extraconal orbital infiltration, which was biopsied. The histopathologic analysis disclosed mild chronic inflammatory infiltrate with thickened fibrous tissue and moderately differentiated lobular carcinoma cells, positive for GATA3 and CK7 markers, with 100% of tumor nuclei expressing estrogen receptors (ER+). A systemic evaluation showed a multicentric nodular formation in both breasts. Further diagnostic assessments unveiled an HR+/HER2- bilateral lobular breast carcinoma with synchronous bilateral orbital metastases. Systemic treatment was initiated with abemaciclib 150mg twice daily and letrozole 2.5mg once a day. However, this regimen was interrupted due to toxicity. After two weeks, treatment was resumed with a reduced abemaciclib dose (100mg twice daily) alongside letrozole, with a reasonable tolerance. Nearly two years after the initial diagnosis of inoperable metastatic cancer, the patient remains on the same systemic treatment regimen with no signs of invasive disease. This case report is the first of a patient presenting with bilateral orbital metastases from bilateral lobular breast cancer, showing an impressive and sustained response to a first-line treatment regimen combining abemaciclib and letrozole. A literature review on bilateral orbital metastases from breast cancer is also presented. [ABSTRACT FROM AUTHOR]

Purpose: Metastatic breast cancer patients are the most prevalent oncology population with advanced disease facing COVID-19 pandemic. Immune responses after mRNA-based vaccination during treatment with CDK4/6 inhibitors or HER2-directed agents remain unclear. We conducted a prospective analysis to elucidate changes in antibody titers and lymphocyte counts following full course of mRNA-BNT162b2 (tozinameran) vaccination in recipients undergoing these targeted therapies. Methods: Patients who had received a booster dosing and had been treated for at least 6 months were eligible. Antibody titers against SARS-CoV-2 spike protein were measured at four subsequent time points. Immunophenotyping of circulating lymphocytes was performed before the third dose of tozinameran and four weeks later to quantify the absolute counts of CD3+CD4+ T-helper cells, CD3+CD8+ T-cytotoxic cells, CD19+ B cells, and CD56+CD16+ NK cells. We also assessed the incidence of breakthrough infections and investigated whether immune changes affect time-to-treatment failure (TTF) after booster vaccination. Results: The current analysis included 69 patients, of whom 38 (55%) and 31 (45%) were being treated with CDK4/6 inhibitors and HER2-targeted therapies, respectively. All participants received a third dose of tozinameran between September 23 and October 7, 2021. Multivariate analysis revealed that CDK4/6 inhibition predicted a significantly impaired humoral response after the booster dose. This detrimental effect was also evident for T-helper cell counts before the third immunization, but it disappeared in the subsequent evaluation. After a median follow-up of 22.3 months, we observed 19 (26%) cases of COVID-19 outbreaks, all experiencing favorable clinical outcomes. Univariate analysis showed a significant association between the onset of SARS-CoV-2 infections and the use of CDK4/6 inhibitors, as well as with an impaired antibody and T- helper cell response. Only the last two covariates remained independent predictors after multivariate testing. Dynamic variations in antibody titers and T-helper cell counts did not affect TTF in multivariate regression analysis. Conclusions: Our results confirm that the immune response to tozinameran is impaired by CDK4/6 inhibitors, increasing the odds of breakthrough infections despite the third vaccine dose. Current evidence recommends maintaining efforts to provide booster immunizations to the most vulnerable cancer patients, including those with advanced breast cancer undergoing CDK4/6 inhibition. [ABSTRACT FROM AUTHOR]

The personalization of therapies in breast cancer has favoured the introduction of new molecular-targeted therapies into clinical practice. Among them, cyclindependent kinases 4 and 6 (CDK4/6) inhibitors have acquired increasing importance, with the approval in recent years of palbociclib, ribociclib, and abemaciclib in combination with endocrine therapy. Currently, no guidelines are available to monitor and manage potential long-term toxicities associated with the use of these drugs. A multidisciplinary panel of European oncologists, was supported by a pharmacologist, a hematologist, a hepatologist and a pulmonologist to discuss the management of long-term toxicities, based on the literature review and their clinical experience. The panel provided detailed roadmaps to manage long-term toxicities associated with the use of CDK4/6 inhibitors in clinical practice. Knowing the frequency and characteristics of the toxicity profile associated with each CDK4/6 inhibitor is important in the decision-making process to match the right drug to the right patient. [ABSTRACT FROM AUTHOR]

Breast cancer is the most commonly diagnosed cancer in women worldwide. Over the past decade, the treatment paradigm for patients with metastatic breast cancer (MBC) has taken an important shift towards better survival and improved quality of life (QOL), especially for those with hormone receptor (HR)-positive diseases which represent the majority of breast cancer subtypes. The introduction of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in the upfront therapy of such patients has resulted in dramatic improvement in progressionfree survival (PFS) and overall survival (OS), too. However, almost all patients would, sooner or later, develop disease progression and necessitate transition to different lines of treatment that may include chemotherapy. The idea of maintaining CDK4/6 inhibitors beyond disease progression seems attractive, as this approach has the potential to improve outcome in this setting despite the fact that the true benefit, in terms of survival, might not carry the same weight as it initially does. Researchers have been investigating potential mechanisms of resistance and identify possible biological markers for response after disease progression. Much of the available data is retrospective; however, few randomized clinical trials were recently published and few more are ongoing, addressing this point. In this paper, we intend to review the available published studies investigating the potential role for keeping CDK4/6 inhibitors in play beyond disease progression. [ABSTRACT FROM AUTHOR]

Background: MBC is a lethal form of breast cancer that arises when cancer cells invade other organs or tissues. The treatment of MBC needs personalized approaches based on the tumor and patient characteristics. The purpose of this paper is to analyze MBC studies from 2002 to 2022 using bibliometrics and to investigate its current situation, main contributors, core journals, highly cited papers, and topic evolution. Materials and methods: We retrieved data from Web of Science Core Collection (WOSCC). Bibliometric analysis of the included literatures mainly used the following tools: the function of "analyze results" and "citation report" in WoS, Microsoft excel 2021, CiteSpace v.6.1. R6, VOSviewer v.1.6.18, BICOMB v.2.04 and gCLUTO v.1.0. Results: We found 12,653 articles on MBC research published in 1, 802 journals by 69, 753 authors from 118 countries. The annual output and citation of MBC articles showed a rising trend over time. The United States was the most influential country in MBC research. The most cited journal in this field was The Journal of Clinical Oncology. And the most cited article was by Slamon DJ. The co-word analysis of keywords divides MBC into six research clusters. The hormone receptor-positive MBC and liquid biopsy of MBC are the frontiers research trends. "CDK4/6 inhibitor" had the highest burst strength. Conclusion: Our bibliometric analysis offers a comprehensive overview of MBC research in the past two decades. It shows the current situation, main contributors, core journals, highly cited papers, and topic evolution of this field. Our study can assist researchers and practitioners to comprehend the development and trends of MBC research and to discover potential directions for future research. [ABSTRACT FROM AUTHOR]

Ribociclib, a cyclin-dependent kinase 4/6 inhibitor, is a novel targeted therapy for advanced-stage breast cancer. Although ribociclib-induced cutaneous side effects have been previously noted, they have not been well documented. Herein, we present a case of ribociclib-induced phototoxicity, which manifested as dyschromia over sun-exposed forearms and neck initially and as bullae formation subsequently. A 71-year-old woman with metastatic breast cancer developed dyschromia after daily treatment with ribociclib (600 mg) for 7 months. Skin biopsy of the pigmented lesion revealed interface dermatitis with melanin incontinence and dyskeratotic cells and ballooning keratinocytes with loss of melanocytes in the basal layer. Further, clefting at the basal layer of epidermis was noted in a more hyperpigmented field. Fontana--Masson staining revealed melanophages in the dermis. Human Melanoma Black-45 staining revealed decreased melanocyte numbers in the epidermis above the cleft. Immunohistochemical analyses revealed activated CD1a+ epidermal Langerhans cells and infiltrating CD4+ and CD8+ T cells in the epidermis and dermis, thereby indicating type IV hypersensitivity that was associated with damage to keratinocytes and melanocytes. To prevent progression of bullous dermatitis, we advised the patient to discontinue ribociclib and prescribed oral and topical prednisolone. Due to the risk of phototoxicity, we educated the patient on sun-protection strategies. The patient's skin lesions subsided during the 2 months of treatment. Phototoxicity with dyschromia is a rare but significant ribociclib-induced cutaneous side effect. Early diagnosis, rapid ribociclib withdrawal, protection from sunlight, and prompt treatment are critical for preventing subsequent severe bullous dermatosis. [ABSTRACT FROM AUTHOR]

Objective: The addition of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) to endocrine therapy impressively improved the outcome of patients with hormone receptor-positive metastatic breast cancer. Despite their great efficacy, not all patients respond to treatment and many of them develop acquired resistance. The aim of this retrospective study was to assess the role of [18F]-FDG PET/CT in predicting PFS and OS in breast cancer patients treated with CDK4/6i. Methods: 114 patients who performed an [18F]-FDG PET/CT scan before (PET1) and 2-6 months (PET2) after starting treatment were retrospectively enrolled. Metabolic response was evaluated by EORTC, PERCIST and Deauville Score and correlated to PFS and OS. Results: In patients who did not progress at PET2 (n = 90), PFS rates were not significantly different between classes of response by EORTC and PERCIST. Conversely, patients showing a Deauville score =3 had a longer PFS (median PFS 42 vs 21.0 months; p = 0.008). A higher total metabolic tumor volume at PET1 (TMTV1) was also associated with a shorter PFS (median 18 vs 42 months; p = 0.0026). TMTV1 and Deauville score were the only independent prognostic factors for PFS at multivariate analysis and their combination stratified the population in four definite classes of relapse risk. Conversely, the above parameters did not affect OS which was only influenced by a progressive metabolic disease at PET2 (3-years survival rate 29.8 vs 84.9%; p<0.0001). Conclusion: TMTV and metabolic response by Deauville score were significant prognostic factors for PFS in patients with breast cancer treated with CDK4/6i. Their determination could help physicians to select patients who may need a closer follow up. [ABSTRACT FROM AUTHOR]

Breast cancer is the most frequently diagnosed cancer in women worldwide. Actually CDK4/6 inhibitor Ribociclib is approved for the treatment of metastatic hormone-positive and human epidermal growth factor receptor 2 (HER 2)- negative breast cancer, but comorbidities like infectious or cardiovascular diseases may limit its use. Case report: A 45-year-old woman was diagnosed with metastatic breast cancer in September 2021; also, her hepatitis screening resulted positive for hepatitis B infection. Patient assumed eradicative therapy for hepatitis and bit after started oncological therapy with Ribociclib. Outcome: Frequent check of hepatological function was observed since start of eradicative therapy; liver transaminases and bilirubin kept to not rise despite start of oncological treatment with Ribociclib. Patient's Performance Status was also not compromised and revaluation at 4, 9 and 13 months showed partial response and then stable disease. Discussion: hepatotoxicity of Ribociclib is reported as a possible side effect, and often positivity for hepatitis is cause of exclusion from therapy; in our case, no hepatotoxicity was noted and patient obtained response in terms of control of both infectious and oncological diseases. [ABSTRACT FROM AUTHOR]

The glucocorticoid receptor (GR) is an important anti-cancer target in lymphoid cancers but has been understudied in solid tumors like lung cancer, although glucocorticoids are often given with chemotherapy regimens to mitigate side effects. Here, we identify a dexamethasone-GR mediated anti-cancer response in a subset of aggressive non-small cell lung cancers (NSCLCs) that harbor Serine/Threonine Kinase 11 (STK11/LKB1) mutations. High tumor expression of carbamoyl phosphate synthase 1 (CPS1) was strongly linked to the presence of LKB1 mutations, was the best predictor of NSCLC dexamethasone (DEX) sensitivity (p < 10-16) but was not mechanistically involved in DEX sensitivity. Subcutaneous, orthotopic and metastatic NSCLC xenografts, biomarker-selected, STK11/LKB1 mutant patient derived xenografts, and genetically engineered mouse models with KRAS/LKB1 mutant lung adenocarcinomas all showed marked in vivo antitumor responses with the glucocorticoid dexamethasone as a single agent or in combination with cisplatin. Mechanistically, GR activation triggers G1/S cell cycle arrest in LKB1 mutant NSCLCs by inducing the expression of the cyclin-dependent kinase inhibitor, CDKN1C/p57(Kip2). All findings were confirmed with functional genomic experiments including CRISPR knockouts and exogenous expression. Importantly, DEX-GR mediated cell cycle arrest did not interfere with NSCLC radiotherapy, or platinum response in vitro or with platinum response in vivo. While DEX induced LKB1 mutant NSCLCs in vitro exhibit markers of cellular senescence and demonstrate impaired migration, in vivo DEX treatment of a patient derived xenograft (PDX) STK11/LKB1 mutant model resulted in expression of apoptosis markers. These findings identify a previously unknown GR mediated therapeutic vulnerability in STK11/LKB1 mutant NSCLCs caused by induction of p57(Kip2) expression with both STK11 mutation and high expression of CPS1 as precision medicine biomarkers of this vulnerability. [ABSTRACT FROM AUTHOR]

Cancer treatment-related adverse events (AEs) are sometimes associated with outcomes for cancer patients, especially with the newest therapies such as target therapy and immunotherapy. A few years ago, the first-line therapy for hormonereceptor-positive metastatic breast cancer (mBC) patients has been deeply changed by the introduction of cyclin-dependent kinase (CDK) 4/6 inhibitors, and now, we are improving our knowledge about their AEs and significance in clinical practice. Here, we report our experience with two cases of vitiligo-like lesions that occur early during treatment with ribociclib. We tried to change the CDK4/6 inhibitor for one patient, but the skin reaction persisted. Both patients retained only the endocrine therapy alone and had an unexpected durable progression-free survival (PFS). Some data on skin toxicities, including vitiligolike lesions by CDK4/6 inhibitors, have recently been reported in the literature, but for the first time, we highlight a possible correlation with improved survival outcomes of patients. Uncovering the etiology of this toxicity, verifying the involvement of the immune system, and demonstrating a possible positive impact in survival represent an intriguing research objective for the near future. [ABSTRACT FROM AUTHOR]

Anti-estrogens or aromatase inhibitors in combination with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are the current standard of care for estrogen receptor-positive (ER+) Her-2 negative metastatic breast cancer. Although these combination therapies prolong progression-free survival compared to endocrine therapy alone, the growth-arrested state of residual tumor cells is clearly transient. Tumor cells that escape what might be considered a dormant or quiescent state and regain proliferative capacity often acquire resistance to further therapies. Our studies are based upon the observation that breast tumor cells arrested by Fulvestrant + Palbociclib enter into states of both autophagy and senescence from which a subpopulation ultimately escapes, potentially contributing to recurrent disease. Autophagy inhibition utilizing pharmacologic or genetic approaches only moderately enhanced the response to Fulvestrant + Palbociclib in ER+ MCF-7 breast tumor cells, slightly delaying proliferative recovery. In contrast, the BET inhibitor/degrader, ARV-825, prolonged the growth arrested state in both p53 wild type MCF-7 cells and p53 mutant T-47D cells and significantly delayed proliferative recovery. In addition, ARV-825 added after the Fulvestrant + Palbociclib combination promoted apoptosis and demonstrated efficacy in resistant RB deficient cell lines. These studies indicate that administration of BET inhibitors/degraders, which are currently being investigated in multiple clinical trials, may potentially improve standard of care therapy in metastatic ER+ breast cancer patients and may further prolong progression-free survival. [ABSTRACT FROM AUTHOR]

Background: Cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) has become the commonest first-line treatment of hormonal receptor positive and human epidermal growth factor receptor 2 negative (HR+/HER2-) metastatic breast cancer (MBC). However, therapy is quite individualized after progression of disease (PD) when CDK4/6i fails. Estrogen receptor (ER) status of metastatic lesions of bone, lung or liver might be different from the primary tumor and biopsy of metastatic lesions was invasive and not always available. Prediction of treatment response after PD of CDK4/6i remains unsolved. 18F-fluoroestradiol (FES) PET/CT could non-invasively reveal ER expression both in primary and metastatic breast cancer and recognize heterogeneity of ER status. Case presentation: A 70-year-old woman with Parkinson's disease, osteoporosis and cardiovascular co-morbidity was diagnosed with HR+/HER2- breast cancer (pT2N2M0, stage IIIa). Three years later, she developed metastases in right lung and pleura with pleural effusion and received palbociclib + letrozole. After 8 months the disease progressed, and 18F-FES PET/CT revealed multiple ER-positive pleural lesions and ER-negative pulmonary nodules after PD and the progression-free survival (PFS) of first-line CDK4/6i was 8months. Sincemost of the metastatic lesions were ER-positive, abemaciclib + fulvestrant were chosen as the second-line CDK4/6i treatment and the PFS was 15 months. Another 18FFES PET/CT showed a new ER-positive pleural mass with multiple ER-negative pulmonary nodules. Since 18F-FES PET/CT revealed that the dominant lesions were still ER-positive, dalpiciclib + exemestane + fulvestrant were prescribed as the third-line CDK4/6i treatment. Currently the patient's disease had been stable for 2 months. Conclusion: This case demonstrated that 18F-FES PET/CT could show ER heterogeneity non-invasively and reveal the treatment responses a predictive imaging tool of serial second- and third-line of CDK4/6i treatments when first-line CDK4/6i failed in HR+/HER2- MBC. So long as the dominant or newly-developed metastatic lesion was ER-positive on 18F-FES PET after first-line CDK4/6i, the patient might show certain therapeutic response towards endocrine-based treatment including second- and third-line of CDK4/6i, and thus increased the time to chemotherapy (TTC). [ABSTRACT FROM AUTHOR]

Background: Cyclin-dependent kinases (CDKs) 4/6 inhibitors are a type of cell cycle regulation that prevents cell proliferation by blocking retinoblastoma protein (Rb) phosphorylation in the G1 to S phase transition. CDK 4/6 inhibitors are currently used mainly in patients with hormone receptor-positive/human epidermal growth factor receptor 2 (HER2) negative breast cancer in combination with endocrine therapy. However, primary or acquired resistance to drugs severely affect drug efficacy. Our study aims at summarizing and visualizing the current research direction and development trend of CDK4/6 inhibitor resistance to provide clinicians and research power with a summary of the past and ideas for the future. Methods: The Web of Science Core Collection and PubMed was searched for all included articles on CDK4/6 inhibitor resistance for bibliometric statistics and graph plotting. The metrological software and graphing tools used were R language version 4.2.0, Bibliometrix 4.0.0, Vosviewer 1.6.18, GraphPad Prism 9, and Microsoft Excel 2019. Results: A total of 1278 English-language articles related to CDK4/6 inhibitor resistance were included in the Web of Science core dataset from 1996-2022, with an annual growth rate of14.56%. In PubMed, a total of 1123 articleswere counted in the statistics, with an annual growth rate of 17.41% Cancer Research is the most included journal (102/1278, 7.98%) with an impact factor of 13.312 and is theQ1 of the Oncology category of the Journal Citation Reports. Professor Malorni Luca from Italy is probably themost contributing author in the current field (Publications 21/1278, 1.64%), while Prof. Turner Nicholas C from the USA is perhaps the most authoritative new author in the field of CDK4/6 inhibitor resistance (Total Citations2584, M-index 1.429). The main research efforts in this field are currently focused on Palbociclib and Abemaciclib. Studies on drug resistance mechanisms or post-drug resistance therapies focus onMEK inhibitors and related pathways, PI3K-AKT-MTOR pathways or inhibitors, EGFR-related pathways, EGFR inhibitors, TKI inhibitors, MAPK pathways and inhibitors, and so on. Conclusion: This study provides researchers with a reliable basis and guidance for finding authoritative references, understanding research trends, and mining research neglect directions. [ABSTRACT FROM AUTHOR]

Background: CDK4/6 inhibitors (CDKi), namely, palbociclib, ribociclib, and abemaciclib, combined with either an aromatase inhibitor (AI) or fulvestrant are the standard first/second line for hormone receptor-positive(HR+)/HER2- negative(neg) metastatic breast cancer (MBC). However, the choice of one specific CDKi is arbitrary and based on the physician's experience with the drug, toxicity profile, and patient's preferences, whereas biomarkers for optimal patient selection have not been established so far. Moreover, upfront chemotherapy is still recommended in case of clinical presentation with visceral crisis, despite no evidence of superior benefit for chemotherapy regimens against CDKi-based regimens. Recent correlative biomarker analyses from pivotal trials of palbociclib and ribociclib showed that HR+/HER2-neg MBC might respond differently according to the molecular intrinsic subtype, with Luminal A and B tumors being sensitive to both CDKi, Basal-like being insensitive to endocrine therapy, irrespective of CDKi, and HER2-enriched tumors showing a benefit only with ribociclib-based therapy. Clinical case: We hereby present a paradigmatic clinical case of a woman affected by a relapsed HR+/HER2-neg MBC with bone and nodal lesions, presenting with a visceral crisis in the form of lymphangitis carcinomatosis and diagnosed with a molecularly HER2-enriched tumor, successfully treated with upfront ribociclib + fulvestrant. The patient experienced a complete symptomatic and radiologic remission of the lymphangitis with a partial response as best response, according to RECIST 1.1 criteria. The progressionfree survival (PFS) was of 20 months, in line with the median PFS observed in the ribociclib + fulvestrant pivotal trial, where, however, patients with visceral crisis had been excluded. Conclusions: This clinical case confirms in the real-world setting that nonluminal subtypes can be found in HR+/HER2-neg disease and may have potential therapeutic implications in the metastatic setting. It also questions the recommendation of upfront chemotherapy in the case of a visceral crisis in the era of CDKi-based regimens. These issues merit further evaluation in prospective and larger studies. [ABSTRACT FROM AUTHOR]

Taxanes and CDK4/6 inhibitors (CDK4/6i) are two families of successful antimitotic drugs used in the treatment of solid tumors. Paclitaxel, representing taxane compounds, has been used either alone or in combination with other agents (commonly carboplatin/cisplatin) in the treatment of many solid tumors including ovarian, breast, lung, prostate cancers, and Kaposi's sarcoma. Paclitaxel has been routinely prescribed in cancer treatment since the 1990s, and its prominent role is unlikely to be replaced in the foreseeable future. Paclitaxel and other taxanes work by binding to and stabilizing microtubules, causing mitotic arrest, aberrant mitosis, and cell death. CDK4/6i (palbociclib, ribociclib, abemaciclib) are relatively new cell cycle inhibitors that have been found to be effective in breast cancer treatment, and are currently being developed in other solid tumors. CDK4/6i blocks cell cycle progression at the G1 phase, resulting in cell death by mechanisms not yet fully elucidated. At first glance, paclitaxel and CDK4/6i are unlikely synergistic agents as both are cell cycle inhibitors that work at different phases of the cell cycle, and few clinical trials have yet considered adding CDK4/6i to existing paclitaxel chemotherapy. However, recent findings suggest the importance of a nonmitotic mechanism of paclitaxel in cancer cell death and pre-clinical data support rationale for a strategic paclitaxel and CDK4/6i combination. In mouse tumor model studies, drug sequencing resulted in differential efficacy, indicating complex biological interactions of the two drugs. This article reviews the rationales of combining paclitaxel with CDK4/6i as a potential therapeutic option in recurrent ovarian cancer. [ABSTRACT FROM AUTHOR]

Platinum-based chemotherapies such as cisplatin are used as first-line treatment for the paediatric tumour neuroblastoma. Although the majority of neuroblastoma tumours respond to therapy, there is a high fraction of high-risk neuroblastoma patients that eventually relapse with increased resistance. Here, we show that one key determinant of cisplatin sensitivity is phosphorylation of the cyclin-dependent kinase inhibitor p21Cip1/Waf1. A panel of eight neuroblastoma cell lines and a TH-MYCN mouse model were investigated for the expression of p21Cip1/Waf1 using RT-qPCR, Western blot, and immunofluorescence. This was followed by investigation of sensitivity towards cisplatin and the p21Cip1/Waf1 inhibitor UC2288. Whereas the cell lines and the mouse model showed low levels of un-phosphorylated p21Cip1/Waf1, the phosphorylated p21Cip1/Waf1 (Thr145) was highly expressed, which in the cell lines correlated to cisplatin resistance. Furthermore, the neuroblastoma cell lines showed high sensitivity to UC2288, and combination treatment with cisplatin resulted in considerably decreased cell viability and delay in regrowth in the two most resistant cell lines, SK-N-DZ and BE(2)-C. Thus, targeting p21Cip1/Waf1 can offer new treatment strategies and subsequently lead to the design of more efficient combination treatments for high-risk neuroblastoma. [ABSTRACT FROM AUTHOR]

Cancer is one of the most serious diseases threatening human health, so it is particularly important to develop effective tumor-targeting drugs. As the first CDK4/6 inhibitor, palbociclib effectively inhibits tumor proliferation by blocking the cell cycle to the G1 phase. 10-HCPT is a Topo I inhibitor; however, its clinical application has been greatly limited due to its high toxicity. Based on the successful development of double target inhibitors, three novel palbociclib derivatives (HP-1, HP-2, and HP-3) were designed and synthesized from Palbociclib and 10-HCPT, and their biological activities were investigated. At first, the possible binding sites of the three compounds to Topo I and CDK4/6 were predicted by molecular docking. Then, we evaluated the anti-proliferative effects of the three palbociclib derivatives. In general, human lung cancer cells were more sensitive to HP-1, HP-2, and HP-3, especially NCI-H460. In addition, cell cycle arrest and apoptosis induction were investigated by flow cytometry. The three palbociclib derivatives, especially HP-1, had obvious cell cycle arrest phenomenon on NCI-H460 cells and induced apoptosis of NCIH460 cells significantly. In the end, it was proved that these three drugs had obvious cyclin-dependent kinase inhibitory activities. In short, all the data showed that HP-1, HP-2, and HP-3 could play anti-cancer roles by acting on dual targets and had the characteristics of high efficiencies and low toxicities, which opened up a new idea for the study of palbociclib derivatives. [ABSTRACT FROM AUTHOR]

Background: Updated evidence was required to compare the efficacy and safety of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) inhibitors for patients with hormone receptor-positive and HER2-negative metastatic breast cancer. Methods: A systematic review and network meta-analysis was conducted utilizing data from randomized controlled trials (RCTs) that contained interventions of CDK4/6 inhibitors or PI3K/AKT/mTOR inhibitors. Progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs) were primary outcomes of interest. Pooled hazard ratios (HRs) and odds ratios (ORs) with 95% credible intervals (CrIs) were used to assess the survival outcomes and safety profiles, respectively. Results: A total of 28 RCTs with 12,129 participants were included. Pooled analysis showed that CDK4/6 inhibitors significantly prolonged PFS than PI3K/AKT/mTOR inhibitors (HR, 0.81; 95% CrI, 0.69-0.94), whereas no significant differences were detected regarding OS. After balancing the treatment lines and metastatic sites, the superiority of CDK4/6 inhibitors only appeared in the visceral and non-visceral subgroups. Among CDK4/6 inhibitors, abemaciclib was significantly better than others in ≥3 grade neutropenia (OR, 0.04; 95% CrI, 0.01-0.15). The incidence of stomatitis and digestive disorders was different among diverse kinds of PI3K/AKT/mTOR inhibitors. Discrepancies appeared regarding TRAEs of hepatotoxicity, diarrhea, and hyperglycemia among different interventions. Conclusions: CDK4/6 inhibitors showed better efficacy in PFS, but the benefits disappeared when taking treatment line into consideration. Specific and discrepant safety profiles were found in two categories of agents. [ABSTRACT FROM AUTHOR]

Chordoma is a rare cancer that grows in the base of the skull and along the mobile spine from remnants of embryonic notochord tissue. The cornerstone of current treatments is surgical excision with adjuvant radiation therapy, although complete surgical removal is not always possible. Chordomas have high rates of metastasis and recurrence, with no approved targeted agents. Selinexor and eltanexor are selective inhibitors of nuclear export (SINE) that prevent the karyopherin protein exportin-1 (XPO1) from shuttling its cargo proteins through nuclear pore complexes out of the nucleus and into the cytoplasm. As cancer cells overexpress XPO1, and many of its cargos include tumor suppressor proteins and complexes bound to oncogene mRNAs, XPO1 inhibition can suppress oncogene translation and restore tumor suppressor protein activity in different cancer types. SINE compounds have exhibited anticancer activity in a wide range of hematological and solid tumor malignancies. Here we demonstrate the preclinical effectiveness of SINE compounds used as single agents or in combination with either the proteasome inhibitor, bortezomib, or the CDK4/6 inhibitor, abemaciclib, against various patientderived xenograft (PDX) mouse models of chordoma, which included clival and sacral chordomas from adult or pediatric patients with either primary or metastatic disease, with either differentiated or poorly differentiated subtypes. SINE treatment significantly impaired tumor growth in all five tested chordoma models, with the selinexor and abemaciclib combination showing the strongest activity (tumor growth inhibition of 78-92%). Immunohistochemistry analysis of excised tumors revealed that selinexor treatment resulted in marked induction of apoptosis and reduced cell proliferation, as well as nuclear accumulation of SMAD4, and reduction of Brachyury and YAP1. RNA sequencing showed selinexor treatment resulted in differences in activated and repressed signaling pathways between the PDX models, including changes in WNT signaling, E2F pathways and glucocorticoid receptor signaling. This is consistent with SINE-compound mediated XPO1 inhibition exhibiting anti-cancer activity through a broad range of different mechanisms in different molecular chordoma subsets. Our findings validate the need for further investigation into selinexor as a targeted therapeutic for chordoma, especially in combination with abemaciclib. [ABSTRACT FROM AUTHOR]

The cell-cycle is a tightly orchestrated process where sequential steps guarantee cellular growth linked to a correct DNA replication. The entire cell division is controlled by cyclin-dependent kinases (CDKs). CDK activation is balanced by the activating cyclins and CDK inhibitors whose correct expression, accumulation and degradation schedule the time-flow through the cell cycle phases. Dysregulation of the cell cycle regulatory proteins causes the loss of a controlled cell division and is inevitably linked to neoplastic transformation. Due to their function as cell-cycle brakes, CDK inhibitors are considered as tumor suppressors. The CDK inhibitors p16INK4a and p15INK4b are among the most frequently altered genes in cancer, including hematopoietic malignancies. Aberrant cell cycle regulation in hematopoietic stem cells (HSCs) bears severe consequences on hematopoiesis and provokes hematological disorders with a broad array of symptoms. In this review, we focus on the importance and prevalence of deregulated CDK inhibitors in hematological malignancies. [ABSTRACT FROM AUTHOR]

Cyclin-dependent kinases, CDK4 and CDK6, are essential in regulating the cell cycle, which is disrupted in cancers like isocitrate dehydrogenase wild-type glioblastoma (GBM). Currently marketed CDK4/6 inhibitors, including abemaciclib, have shown preclinical efficacy in solid tumors, but factors such as poor blood-brain barrier (BBB) penetration limit their efficacy in GBM. GLR2007 is an investigational CDK4/6 inhibitor with the potential for improved BBB penetration. In vitro assays were used to assess the potency and inhibition of CDK4/6 enzymatic activity of GLR2007. Using in vivo assays, the distribution of radiolabeled GLR2007 in rats was determined through quantitative whole-body autoradiography. The antitumor efficacy of GLR2007 was evaluated in human GBM and breast cancer orthotopic mice xenograft models, and human lung, colorectal, and liver cancer in a subcutaneous xenograft model. In tumor cell line proliferation assays, GLR2007 inhibited proliferation at lower concentration values than abemaciclib in 19 of 20 GBM, five of seven breast, 20 of 21 lung, and 24 of 24 liver cancer cell lines. Total levels of radiolabeled GLR2007 in the brains of rats exceeded those in plasma by 2.3-4.5-fold from 2-6 hours after dosing. A xenograft model showed that, compared with vehicle control, 50 mg/kg GLR2007 induced 95.9% tumor growth inhibition (TGI) (P<0.001) in GBM orthotopic xenografts, 81.4% TGI (P=0.037) in breast cancer orthotopic xenografts, and 91.5% TGI (P<0.001) in colorectal cancer subcutaneous xenografts. These studies show possible BBB penetration of GLR2007 and demonstrate its potential as a CDK4/6 inhibitor for the treatment of solid tumors, including GBM. [ABSTRACT FROM AUTHOR]

Introduction: Sarcomas are rare heterogeneous malignant tumors that originate and develop in soft tissue or bone. Effective treatment for sarcomas is still limited to traditional chemotherapy and surgery that are often ineffective for recurrent disease. Cyclin-dependent kinases (CDKs) promote abnormal cell cycling and cell division in many cancers including sarcomas. Therefore, our hypothesis was that CDK inhibitors may be useful candidates for sarcoma treatment. Patientderived orthotopic xenograft (PDOX) mouse models mimic the clinical disease for all major cancer types and have identified effective treatments that hold much clinical promise. The present report reviews sarcoma PDOX models that we have established for their potential to discover effective combination treatments based on CDK inhibitors for recalcitrant sarcoma. Methods: We have previously reported six sarcoma PDOX studies evaluating the CDK inhibitor palbociclib on sarcoma, including osteosarcoma, Ewing sarcoma, de-differentiated liposarcoma, and peritoneal metastatic leiomyosarcoma. Results: Palbociclib monotherapy significantly inhibited, but not regressed, the PDOX growth of osteosarcoma, Ewing sarcoma, de-differentiated liposarcoma, and peritoneal metastatic leiomyosarcoma. A combination of palbociclib and a mammalian target of rapamycin (mTOR) inhibitor, everolimus, significantly inhibited, but did not regress, the PDOX growth of osteosarcoma. Combinations of palbociclib with a multikinase inhibitor, sorafenib, and palbociclib combined with recombinant methioninase were effective and regressed the osteosarcoma and de-differentiated liposarcoma PDOX models, respectively. Conclusions: Novel effective drug combinations using the CDK inhibitor palbociclib were identified in PDOX models of the major types of sarcomas. Methionine restriction effected by methioninase increased the efficacy of palbociclib. Combination therapy with palbociclib is a promising future strategy for improved sarcoma therapy in the clinic. [ABSTRACT FROM AUTHOR]

ThezincfingerproteinGrowthFactor Independence1 (GFI1) actsasatranscriptional repressor regulating differentiation of myeloid and lymphoid cells. A single nucleotide polymorphism of GFI1, GFI1-36N, has a prevalence of 7% in healthy Caucasiansand15%in acutemyeloidleukemia (AML)patients, hencemostprobably predisposing to AML. One reason for this is that GFI1-36N differs from thewildtype form GFI1-36S regarding its ability to induce epigenetic changes resulting in a derepression of oncogenes. Using proteomics, immunofluorescence, and immunoblotting we have now gained evidence that murine GFI1-36N leukemic cells exhibit a higher protein level of the pro-proliferative protein arginine Nmethyltransferase 5 (PRMT5) as well as increased levels of the cell cycle propagating cyclin-dependent kinases 4 (CDK4) and 6 (CDK6) leading to a faster proliferation of GFI1-36N leukemic cells in vitro. As a therapeutic approach, we subsequently treated leukemic GFI1-36S and GFI1-36N cells with the CDK4/6 inhibitor palbociclib and observed that GFI1-36N leukemic cells were more susceptible to this treatment. The findings suggest that presence of the GFI1-36N variant increases proliferation of leukemic cells and could possibly be amarker for a specific subset of AML patients sensitive to CDK4/6 inhibitors such as palbociclib. [ABSTRACT FROM AUTHOR]

The cell-cycle is a tightly orchestrated process where sequential steps guarantee cellular growth linked to a correct DNA replication. The entire cell division is controlled by cyclin-dependent kinases (CDKs). CDK activation is balanced by the activating cyclins and CDK inhibitors whose correct expression, accumulation and degradation schedule the time-flow through the cell cycle phases. Dysregulation of the cell cycle regulatory proteins causes the loss of a controlled cell division and is inevitably linked to neoplastic transformation. Due to their function as cell-cycle brakes, CDK inhibitors are considered as tumor suppressors. The CDK inhibitors p16INK4a and p15INK4b are among the most frequently altered genes in cancer, including hematopoietic malignancies. Aberrant cell cycle regulation in hematopoietic stem cells (HSCs) bears severe consequences on hematopoiesis and provokes hematological disorders with a broad array of symptoms. In this review, we focus on the importance and prevalence of deregulated CDK inhibitors in hematological malignancies.

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer with a poor prognosis and limited treatment options. Considering that alterations of the CDK4/6-cyclin D-Rb pathway occur frequently in HCC, we tested the efficacy of two CDK4/6 inhibitors, abemaciclib and ribociclib, in combination with lenvatinib, a multi-kinase inhibitor approved as first-line therapy for advanced HCC, in a panel of HCC Rb-expressing cell lines. The simultaneous drug combinations showed a superior anti-proliferative activity as compared with single agents or sequential schedules of treatment, either in short or in long-term experiments. In addition, the simultaneous combination of abemaciclib with lenvatinib reduced 3D cell growth, and impaired colony formation and cell migration. Mechanistically, these growth-inhibitory effects were associated with a stronger down-regulation of c-myc protein expression. Depending on the HCC cell model, reduced activation of MAPK, mTORC1/p70S6K or src/FAK signaling was also observed. Abemaciclib combined with lenvatinib arrested the cells in the G1 cell cycle phase, induced p21 accumulation, and promoted a stronger increase of cellular senescence, associated with elevation of β-galactosidase activity and accumulation of ROS, as compared with single treatments. After drug withdrawal, the capacity of forming colonies was significantly impaired, suggesting that the anti-tumor efficacy of abemaciclib and lenvatinib combination was persistent. Our pre-clinical results demonstrate the effectiveness of the simultaneous combination of CDK4/6 inhibitors with lenvatinib in HCC cell models, suggesting that this combination may be worthy of further investigation as a therapeutic approach for the treatment of advanced HCC. [ABSTRACT FROM AUTHOR]

Meningiomas are the most common non-metastatic brain tumors, and although the majority are relatively slow-growing and histologically benign, a subset of meningiomas are aggressive and remain challenging to treat. Despite a standard of care that includes surgical resection and radiotherapy, and recent advances in meningioma molecular grouping, there are no systemic medical options for patients with meningiomas that are resistant to standard interventions. Misactivation of the cell cycle at the level of CDK4/6 is common in high-grade or molecularly aggressive meningiomas, and CDK4/6 has emerged as a potential target for systemic meningioma treatments. In this review, we describe the preclinical evidence for CDK4/6 inhibitors as a treatment for high-grade meningiomas and summarize evolving clinical experience with these agents. Further, we highlight upcoming clinical trials for patients meningiomas, and discuss future directions aimed at optimizing the efficacy of these therapies and selecting patients most likely to benefit from their use. [ABSTRACT FROM AUTHOR]

Background: Cyclin-dependent kinase 4/6 inhibitors are a standard treatment for patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). However, real-world data on effectiveness in patients with liver or lung metastatic disease is limited. This study compared outcomes of palbociclib plus letrozole versus letrozole alone in patients with HR+/HER2- MBC with lung or liver metastasis treated in routine clinical practice in the United States. Methods: This retrospective analysis used Flatiron Health's database of electronic health records. Women with HR+/HER2- MBC and liver or lung metastasis received first-line palbociclib plus letrozole or letrozole alone between February 2015 and February 2019. Real-world progression-free survival (rwPFS) was defined as time from start of treatment to death or disease progression. Stabilized inverse probability treatment weighting (sIPTW) was used to balance baseline demographic and clinical characteristics between palbociclib plus letrozole versus letrozole cohorts. Cox proportional-hazards models were used to estimate the effectiveness of palbociclib plus letrozole versus letrozole alone in rwPFS and overall survival (OS). Results: The study included 353 patients with lung metastasis, 123 with liver metastasis, and 75 with both. After sIPTW, palbociclib plus letrozole versus letrozole alone was significantlly associated with prolonged rwPFS (hazard ratio (HR), 0.56) and OS (HR, 0.58) (both p<0.001) in all patients. Palbociclib plus letrozole compared with letrozole alone demonstrated a median rwPFS of 16.5 versus 10.5 months, respectively (adjusted HR, 0.52; P<0.001), a median OS of not reached versus 40.3 months (adjusted HR, 0.60; P<0.01) in patients with lung metastasis, and median OS of 30.1 versus 16.8 months (adjusted HR, 0.56; P<0.03 in patients with liver metastasis. In patients with liver metastasis, palbociclib plus letrozole had a median rwPFS of 10.7 months versus 8.0 months in the letrozole alone cohort (adjusted HR, 0.70; P=0.12). Conclusions: In this real-world population, palbociclib in combination with letrozole is associated with improved outcomes compared with letrozole alone for patients with HR+/HER2- MBC and liver or lung metastasis in the first-line setting. The findings support first-line palbociclib in combination with an aromatase inhibitor as standard of care for HR+/HER2- MBC regardless of visceral disease. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy is the most promising treatment in triple-negative breast cancer (TNBC), and its efficiency is largely dependent on the intra-tumoral immune cells infiltrations. Thus, novel ways to assist immunotherapy by increasing immune cell infiltrations were highly desirable. Methods: To find key immune-related genes and discover novel immune-evoking molecules, gene expression profiles of TNBC were downloaded from Gene Expression Omnibus (GEO). Single-sample gene set enrichment analysis (ssGSEA) and Weighted Gene Co-expression Network Analysis (WGCNA) were conducted to identified hub genes. The CMap database was used subsequently to predicate potential drugs that can modulate the overall hub gene expression network. In vitro experiments were conducted to assess the anti-tumor activity and the pyroptosis phenotypes induced by GW-8510. Results: Gene expression profiles of 198 TNBC patients were downloaded from GEO dataset GSE76124, and ssGSEA was used to divide them into Immune Cell Proficiency (ICP) group and Immune Cell Deficiency (ICD) group. Hub differential expressed gene modules between two groups were identified by WGCNA and then annotated by Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. A cyclin-dependent kinase (CDK) 2 inhibitor, GW-8510 was then identified by the CMap database and further investigated. Treatment with GW-8510 resulted in potent inhibition of TNBC cell lines. More importantly, in vitro and in vivo studies confirmed that GW-8510 and other CDK inhibitors (Dinaciclib, and Palbociclib) can induce pyroptosis by activating caspase-3 and GSDME, which might be the mechanism for their immune regulation potentials. Conclusion: GW-8510, as well as other CDK inhibitors, might serve as potential immune regulators and pyroptosis promotors in TNBC. [ABSTRACT FROM AUTHOR]

The cyclin D-CDK4/6 complexes play a pivotal role in controlling the cell cycle. Deregulation in cyclin D-CDK4/6 pathway has been described in many types of cancer and it invariably leads to uncontrolled cell proliferation. Many efforts have been made to develop a target therapy able to inhibit CDK4/6 activity. To date, three selective CDK4/6 small inhibitors have been introduced in the clinic for the treatment of hormone positive advanced breast cancer patients, following the impressive results obtained in phase III clinical trials. However, since their approval, clinical evidences have demonstrated that about 30% of breast cancer is intrinsically resistant to CDK4/6 inhibitors and that prolonged treatment eventually leads to acquired resistance in many patients. So, on one hand, clinical and preclinical studies fully support to go beyond breast cancer and expand the use of CDK4/6 inhibitors in other tumor types; on the other hand, the question of primary and secondary resistance has to be taken into account, since it is now very clear that neoplastic cells rapidly develop adaptive strategies under treatment, eventually resulting in disease progression. Resistance mechanisms so far discovered involve both cell-cycle and non-cell-cycle related escape strategies. Full understanding is yet to be achieved but many different pathways that, if targeted, may lead to reversion of the resistant phenotype, have been already elucidated. Here, we aim to summarize the knowledge in this field, focusing on predictive biomarkers, to recognize intrinsically resistant tumors, and therapeutic strategies, to overcome acquired resistance. [ABSTRACT FROM AUTHOR]

Background: Recent clinical trials of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in human lung adenocarcinoma (LUAD) have not achieved satisfactory results. The disappointing results of single-drug treatments have prompted studies about synergistic therapies of CDK4/6i with other drugs. We aimed to test the anti-tumor effect of ribociclib (a CDK4/6i) combined with pemetrexed on LUAD and the potential mechanisms. Methods: Cell lines were exposed to ribociclib and pemetrexed at different doses. Antitumor effects were measured using growth inhibition. Cell cycle distribution and apoptosis were evaluated using flow cytometry. Cell migration and invasion were measured using wound healing and transwell invasion assays, respectively. The expression levels of proteins were analyzed using western blotting. Mice xenograft models were used for validation in vivo. Results: Synergism was associated with a combination of cell cycle effects from both agents. Cell cycle analysis revealed that pemetrexed blocked cells in the S phase, whereas ribociclib arrested cells in the G1 phase. Concomitant treatment with pemetrexed and ribociclib resulted in a significantly stronger antitumor ability than treatment alone. We also found that ribociclib strongly enhanced the pro-apoptotic activity of pemetrexed via the caspase/bcl-2 signaling pathway. In addition, we report for the first time that combination treatment with ribociclib and pemetrexed significantly inhibits the migration and invasion of LUAD cells. Conclusions: Combining ribociclib and pemetrexed showed a powerful ability to inhibit cancer proliferation, invasion, and metastasis, and it holds potential as a novel effective combinative therapy for patients with LUAD. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma (CCA) is one of the most difficult to treat cancers, and its nature of being largely refractory to most, if not all, current treatments results in generally poor prognosis and high mortality. Efficacious alternative therapies that can be used ubiquitously are urgently needed. Using acquired vulnerability screening, we observed that CCA cells that reprofile and proliferate under CDK4/6 inhibition became vulnerable to ribosomal biogenesis stress and hypersensitive to the anti-ribosome chemotherapy oxaliplatin. CCA cells overexpress the oncogenic ribosomal protein RPL29 under CDK4/6 inhibition in a manner that correlated with CDK4/6 inhibitor resistance. Depletion of RPL29 by small interfering RNAs (siRNAs) restored the sensitivity of CCA cells to CDK4/6 inhibition. Oxaliplatin treatment suppressed the RPL29 expression in the CDK4/6 inhibitor treated CCA cells and triggered RPL5/11-MDM2-dependent p53 activation and cancer apoptosis. In addition, we found that combination treatment with oxaliplatin and the CDK4/6 inhibitor palbociclib synergistically inhibited both parental and CDK4/6 inhibitor-resistant CCA, and prevented the emergence of CDK4/6 and oxaliplatin-resistant CCA. This drug combination also exerted suppressive and apoptosis effects on CCA in the in vitro 3-dimensional culture, patient-derived organoid, and in vivo xenograft CCA models. These results suggest the combination of the CDK4/6 inhibitor palbociclib and the anti-ribosome drug oxaliplatin as a potentially promising treatment for cholangiocarcinoma. [ABSTRACT FROM AUTHOR]

Background: Infiltrating bladder urothelial carcinoma is the most common bladder malignancy with limited therapeutic options and poor prognosis. Identifying new therapeutic targets or strategies has important clinical significance. The data from public sources indicate poor prognosis in urothelial carcinoma cases with high CDK6 mRNA levels. Furthermore, studies have shown that CDK6 expression is elevated in urothelial carcinoma tissue compared to the surrounding urothelium, thus presenting a case for performing CDK4/6 inhibitor targeted research in urothelial carcinoma. However, a phase II trial showed that CDK4/6 inhibitors are not effective for advanced urothelial carcinoma, suggesting that case screening is important for targeted therapy. Objective: Immunohistochemistry (IHC) is simple and easy to perform and can be used to screen urothelial carcinoma cases with high CDK6 expression in clinical practice. The aim of this study was to determine the CDK6 expression threshold for positive cases. Methods: We evaluated the correlation between the H-score of CDK6 protein expression and survival or CDK6 mRNA level using RNA sequencing. The effects of different CDK4/6 inhibitors were tested on bladder carcinoma cell lines with different CDK6 expression levels. Results: The H-score, which predicts poor prognosis and reflects a high CDK6 mRNA level, was determined as the selection criterion for positive cases. Furthermore, we found that urothelial carcinoma cell lines with higher CDK6 expression levels displayed greater sensitivity to CDK4/6 inhibitors than cells with lower expression levels. Conclusions: IHC staining for CDK6 protein in urothelial carcinoma is proposed as a promising screening platform for CDK4/6 inhibitor targeted therapy. [ABSTRACT FROM AUTHOR]

Lung squamous cell carcinoma (LUSC) remains as a major cause of cancer-associated mortality with few therapeutic options. Continued research on new driver genes is particularly important. FGF19, a fibroblast growth factor, is frequently observed as amplified in human LUSC, which is also associated with multiple genomic gains and losses. However, the importance of these associated changes is largely unknown. In this study, we aimed to clarify a novel mechanism that link neighboring oncogene co-amplification in the development of LUSC. We found that FGF19 was co-amplified and co-expressed with its neighboring gene CCND1 in a subset of LUSC patients and associated with poor prognosis. Moreover, FGF19 combined with CCND1 promoted the cell cycle progression of LUSC cells. Mechanistically, FGF19 also enhanced CCND1 expression by activating FGFR4-ERK1/2 signaling and strengthening CCND1-induced phosphorylation and inactivation of retinoblastoma (RB). In a murine model of lung orthotopic cancer, knockdown of CCND1 was found to prolong survival by attenuating FGF19-induced cell proliferation. Furthermore, the combination treatment of the FGFR4 inhibitor BLU9931 and the CDK4/6 inhibitor palbociclib potentiated the growth inhibition and arrested cells in G1 phase. In vivo , co-targeting FGFR4 and CDK4/6 also showed marked inhibition of tumor growth than single agent treatment. These findings further elucidate the oncogenic role of FGF19 in LUSC and provide insights into how the co-amplification of neighboring genes synergistically function to promote cancer growth, and combined inhibition against both FGF19 and CCND1 is more effective. [ABSTRACT FROM AUTHOR]

Purpose: The LORDSHIPS study aimed to explore the safety and efficacy of a novel fully oral triplet combination of dalpiciclib (a potent cyclin-dependent kinase 4/6 inhibitor), pyrotinib (a HER2 tyrosine kinase inhibitor) and endocrine therapy letrozole in patients with HER2-positive, hormone receptor (HR)-positive metastatic breast cancer (MBC) in the front-line setting. Patients and Methods: Postmenopausal women with HER2-positive, HR-positive MBC were recruited in the dose-finding phase Ib trial. A standard 3 + 3 design was used to determine safety, tolerability, and recommended phase II dose (RP2D) for the combination. Results: A total of 15 patients were enrolled to three dose combination cohorts (letrozole/pyrotinib/dalpiciclib, level/I: 2.5/400/125 mg, n=5; level/L1: 2.5/400/100 mg, n=6; level/L2: 2.5/320/125 mg, n=4). Three patients experienced dose-limiting toxicities (level/I, n=2; level/L1, n=1) and level/L2 was identified as RP2D. The most frequent grade 3-4 adverse events were neutropenia (46.7%), leukopenia (40.0%), oral mucositis (26.7%) and diarrhea (20.0%). The confirmed objective response rate (ORR) was 66.7% (95% CI: 38.4% to 88.2%). The confirmed ORR of study treatment as first line (1L) and second line (2L) HER2-targeted therapy was 85.7% (6/7) and 50.0% (4/8), respectively. Median progression-free survival (PFS) was 11.3 months (95% CI: 5.3 months to not reached). PFS in 1L setting was not reached yet, while PFS in 2L setting was 10.9 months (95% CI: 1.8 to 13.7 months). Conclusions: The fully oral combination of dalpiciclib, pyrotinib and letrozole is a promising chemotherapy-sparing treatment option for HER2-positive, HR-positive MBC patients. The planned dose-expansion phase II study is ongoing. Clinical Trial Registration: ClinicalTrials.gov , identifier NCT03772353. [ABSTRACT FROM AUTHOR]

The recent addition of cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors to endocrine therapy has remarkably improved the outcome of patients affected with hormone receptor positive (HR+), human epidermal grow factor receptor 2 negative (HER2 -) advanced breast cancer (ABC). Ribociclib showed to be effective across most subgroups, regardless of the number and the site of metastasis. Up to 10% of patients with ABC, reported an oligometastatic condition, recently defined as a slow-volume metastatic disease with limited number and size of metastatic lesions (up to 5 and not necessarily in the same organ), potentially amenable for local treatment, aimed at achieving a complete remission status. Despite the wide use of CDK4/6 inhibitors in HR+, HER2-, ABC treatment, data regarding both locally advanced, inoperable disease and oligometastatic conditions are still poor. We reported a review and case series of HR+, HER2-, ABC patients treated with ribociclib as first-line therapy, for a locally advanced and oligometastatic conditions, reporting an impressive response and good safety profile. [ABSTRACT FROM AUTHOR]

Background: While molecular insights to diffuse lower-grade glioma (dLGG) have improved the basis for prognostication, most established clinical prognostic factors come from the pre-molecular era. For instance, WHO grade as a predictor for survival in dLGG with isocitrate dehydrogenase (IDH) mutation has recently been questioned. We studied the prognostic role of WHO grade in molecularly defined subgroups and evaluated earlier used prognostic factors in the current molecular setting. Material and Methods: A total of 253 adults with morphological dLGG, consecutively included between 2007 and 2018, were assessed. IDH mutations, codeletion of chromosomal arms 1p/19q, and cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletions were analyzed. Results: There was no survival benefit for patients with WHO grade 2 over grade 3 IDH -mut dLGG after exclusion of tumors with known CDKN2A/B homozygous deletion (n=157) (log-rank p=0.97). This was true also after stratification for oncological postoperative treatment and when astrocytomas and oligodendrogliomas were analyzed separately. In IDH- mut astrocytomas, residual tumor volume after surgery was an independent prognostic factor for survival (HR 1.02; 95% CI 1.01–1.03; p=0.003), but not in oligodendrogliomas (HR 1.02; 95% CI 1.00–1.03; p=0.15). Preoperative tumor size was an independent predictor in both astrocytomas (HR 1.03; 95% CI 1.00–1.05; p=0.02) and oligodendrogliomas (HR 1.05; 95% CI 1.01–1.09; p=0.01). Age was not a significant prognostic factor in multivariable analyses (astrocytomas p=0.64, oligodendrogliomas p=0.08). Conclusion: Our findings suggest that WHO grade is not a robust prognostic factor in molecularly well-defined dLGG. Preoperative tumor size remained a prognostic factor in both IDH -mut astrocytomas and oligodendrogliomas in our cohort, whereas residual tumor volume predicted prognosis in IDH -mut astrocytomas only. The age cutoffs for determining high risk in patients with IDH -mut dLGG from the pre-molecular era are not supported by our results. [ABSTRACT FROM AUTHOR]

Background: Alternative splicing (AS) is a gene regulatory mechanism that drives protein diversity. Dysregulation of AS is thought to play an essential role in cancer initiation and development. This study aimed to construct a prognostic signature based on AS and explore the role in the tumor immune microenvironment (TIME) in lung adenocarcinoma. Methods: We analyzed transcriptome profiling and clinical lung adenocarcinoma data from The Cancer Genome Atlas (TCGA) database and lists of AS-related and immune-related signatures from the SpliceSeq. Prognosis-related AS events were analyzed by univariate Cox regression analysis. Gene set enrichment analyses (GSEA) were performed for functional annotation. Prognostic signatures were identified and validated using univariate and multivariate Cox regression, LASSO regression, Kaplan–Meier survival analyses, and proportional hazards model. The context of TIME in lung adenocarcinoma was also analyzed. Gene and protein expression data of Cyclin-Dependent Kinase Inhibitor 2A (CDKN2A) were obtained from ONCOMINE and Human Protein Atlas. Splicing factor (SF) regulatory networks were visualized. Results: A total of 19,054 survival-related AS events in lung adenocarcinoma were screened in 1,323 genes. Exon skip (ES) and mutually exclusive exons (ME) exhibited the most and fewest AS events, respectively. Based on AS subtypes, eight AS prognostic signatures were constructed. Patients with high-risk scores were associated with poor overall survival. A nomogram with good validity in prognostic prediction was generated. AUCs of risk scores at 1, 2, and 3 years were 0.775, 0.736, and 0.759, respectively. Furthermore, the prognostic signatures were significantly correlated with TIME diversity and immune checkpoint inhibitor (ICI)-related genes. Low-risk patients had a higher StromalScore, ImmuneScore, and ESTIMATEScore. AS-based risk score signature was positively associated with CD8+ T cells. CDKN2A was also found to be a prognostic factor in lung adenocarcinoma. Finally, potential functions of SFs were determined by regulatory networks. Conclusion: Taken together, our findings show a clear association between AS and immune cell infiltration events and patient outcome, which could provide a basis for the identification of novel markers and therapeutic targets for lung adenocarcinoma. SF networks provide information of regulatory mechanisms. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers with high mortality worldwide. Type 2 diabetes mellitus (T2D), known as a risk factor of CRC, can promote the deterioration of CRC, but the underlying mechanism is elusive. In this study, we aimed to reveal the relationship between CRC and T2D from the perspective of small-molecule metabolism. First, a list of common dysregulated metabolites in CRC and T2D was obtained by retrieving existing metabolomics publications. Among these metabolites, oleic acid (OA) was found to be able to promote the proliferation and migration of colon carcinoma cell HCT116. Further experiments proved that insulin could significantly strengthen this promotion and showed a synergistic effect with OA. Mechanism study found that OA and insulin acted synergistically through the extracellular signal-regulated kinase (ERK)1/2/c-Myc/cyclin D1 pathway. In addition, the combination of ERK1/2 inhibitor SCH772984 and cyclin-dependent kinase (CDK)4/6 inhibitor palbociclib showed a remarkable inhibitory effect on tumor growth in vivo. Taken together, the current study found that OA plays an important role in CRC development by using a functional metabolomics approach. More importantly, insulin and OA were confirmed to synergistically promote the deterioration of CRC in vitro and in vivo via ERK1/2/c-Myc/cyclin D1 pathway. Our findings may shed light on CRC treatment among the T2D population. [ABSTRACT FROM AUTHOR]

Malignant pleural mesothelioma is an aggressive cancer, heterogeneous in its presentation and behaviour. Despite an increasing knowledge about molecular markers and their diagnostic and prognostic value, they are not used as much as they might be for treatment allocation. It has been recently reported that mesothelioma cells that lack BAP1 (BRCA1 Associated Protein) are sensitive to inhibition of the EZH2 (Enhancer of Zeste Homolog 2) histone methyltransferase. Since we observed strong H3K27me3 (histone H3 lysine 27 trimetylation) immunoreactivity in BAP1 wild-type mesothelioma biopsies, we decided to characterize in vitro the response/resistance of BAP1 wild-type mesothelioma cells to the EZH2 selective inhibitor, EPZ-6438. Here we demonstrate that BAP1 wild-type mesothelioma cells were rendered sensitive to EPZ-6438 upon SIRT1 (Sirtuin 1) silencing/inhibition or when cultured as multicellular spheroids, in which SIRT1 expression was lower compared to cells grown in monolayers. Notably, treatment of spheroids with EPZ-6438 abolished H3K27me3 and induced the expression of CDKN2A (Cyclin-Dependent Kinase Inhibitor 2A), causing cell growth arrest. EPZ-6438 treatment also resulted in a rapid and sustained induction of the genes encoding HIF2α (Hypoxia Inducible Factor 2α), TG2 (Transglutaminase 2) and IL-6 (Interleukin 6). Loss of CDKN2 is a common event in mesothelioma. CDKN2A silencing in combination with EPZ-6438 treatment induced apoptotic death in mesothelioma spheroids. In a CDKN2A wild-type setting apoptosis was induced by combining EPZ-6438 with 1-155, a TG2 selective and irreversible inhibitor. In conclusion, our data suggests that the expression of CDKN2A predicts cell fate in response to EZH2 inhibition and could potentially stratify tumors likely to undergo apoptosis. [ABSTRACT FROM AUTHOR]

Basal cell carcinoma (BCC) is a locally invasive epithelial cancer that is primarily driven by the Hedgehog (HH) pathway. Advanced BCCs are a critical subset of BCCs that frequently acquire resistance to Smoothened (SMO) inhibitors and identifying pathways that bypass SMO could provide alternative treatments for patients with advanced or metastatic BCC. Here, we use a combination of RNA-sequencing analysis of advanced human BCC tumor-normal pairs and immunostaining of human and mouse BCC samples to identify a PI3K pathway expression signature in BCC. Pharmacological inhibition of PI3K activity in BCC cells significantly reduces cell proliferation and HH signaling. However, treatment of Ptch1fl/fl ; Gli1 - CreERT2 mouse BCCs with the PI3K inhibitor BKM120 results in a reduction of tumor cell growth with no significant effect on HH signaling. Downstream PI3K components aPKC and Akt1 showed a reduction in active protein, whereas their substrate, cyclin-dependent kinase inhibitor p21, showed a concomitant increase in protein stability. Our results suggest that PI3K promotes BCC tumor growth by kinase-induced p21 degradation without altering HH signaling. [ABSTRACT FROM AUTHOR]

Background: Micropapillary adenocarcinoma is one of the most aggressive histologic subtypes of lung adenocarcinoma (LADC), and even a minor proportion of micropapillary component (MPC) within the LADC could contribute to poor prognosis. Comprehensive analysis of genetic and immunological features of LADC with different percentages of MPC would help better understand cancer biology of this LADC subtype and direct future treatments. Methods: We performed next-generation sequencing (NGS) for a discovery cohort of 43 LADC patients whose tumors were micro-dissected to separate MPC and non-MPC lesions and a reference cohort of 113 LADC patients. MPC-enriched genetic alterations that were detected in the discovery cohort were then confirmed using a validation cohort of 183 LADC patients. Immunological staining was also conducted on the MPC-containing samples in the discovery cohort. Results: Tumors with a higher percentage of MPC tended to harbor more tumor mutation burdens (TMBs) and chromosome instability (CIN). Some rare genetic events may serve as the genetic landscape to drive micropapillary tumor progression. Specifically, alterations in transcription termination factor 1 (TTF1), brain-specific angiogenesis inhibitor 3 (BAI3), mammalian target of rapamycin (MTOR), and cyclin-dependent kinase inhibitor 2A (CDKN2A) were cross-validated to be enriched in MPC-contained LADC. Additionally, tumors with a higher percentage of MPC were associated with a higher percentage of CD4+, CD8+, and PD-L1+ staining, and some genetic changes that were enriched in MPC, including MET amplification and MTOR mutation, were correlated with increased PD-L1 expression. Conclusion: We identified multiple novel MPC-enriched genetic changes that could help us understand the nature of this aggressive cancer subtype. High MPC tumors tended to have elevated levels of TMBs, T cell infiltration, and immunosuppression than low MPC tumors, implying the potential link between MPC content and sensitivity to immunotherapy. [ABSTRACT FROM AUTHOR]