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Simple Summary: We identified the TAM (Tyro3, Axl, and MerTK) RTKs as a crucial therapeutic vulnerability in Triple-negative breast cancer (TNBC). We show that targeting the TAM receptors with a novel inhibitor, sitravatinib, significantly sensitizes TNBC to CDK4/6 inhibitors. Given the roles of the TAM receptors in promoting the creation of an immunosuppressive tumor microenvironment (TME), we further demonstrate that the combination of CDK4/6 inhibitor abemaciclib and sitravatinib modifies the immune landscape of TNBC to favor immune checkpoint blockade. Triple-negative breast cancer (TNBC) is the most aggressive subtype with high metastasis and mortality rates. Given the lack of actionable targets such as ER and HER2, TNBC still remains an unmet therapeutic challenge. Despite harboring high CDK4/6 expression levels, the efficacy of CDK4/6 inhibition in TNBC has been limited due to the emergence of resistance. The resistance to CDK4/6 inhibition is mainly mediated by RB1 inactivation. Since our aim is to overcome resistance to CDK4/6 inhibition, in this study, we primarily used the cell lines that do not express RB1. Following a screening for activated receptor tyrosine kinases (RTKs) upon CDK4/6 inhibition, we identified the TAM (Tyro3, Axl, and MerTK) RTKs as a crucial therapeutic vulnerability in TNBC. We show that targeting the TAM receptors with a novel inhibitor, sitravatinib, significantly sensitizes TNBC to CDK4/6 inhibitors. Upon prolonged HER2 inhibitor treatment, HER2+ breast cancers suppress HER2 expression, physiologically transforming into TNBC-like cells. We further show that the combined treatment is highly effective against drug-resistant HER2+ breast cancer as well. Following quantitative proteomics and RNA-seq data analysis, we extended our study into the immunophenotyping of TNBC. Given the roles of the TAM receptors in promoting the creation of an immunosuppressive tumor microenvironment (TME), we further demonstrate that the combination of CDK4/6 inhibitor abemaciclib and sitravatinib modifies the immune landscape of TNBC to favor immune checkpoint blockade. Overall, our study offers a novel and highly effective combination therapy against TNBC and potentially treatment-resistant HER2+ breast cancer that can be rapidly moved to the clinic. [ABSTRACT FROM AUTHOR]

Simple Summary: This position paper aims to address specific clinical questions regarding the use of cyclin-dependent kinase 4/6 inhibitors in elderly patients with early or advanced breast cancer. Its objectives are to delineate the current state of knowledge regarding the efficacy of these treatments in the elderly population and their tolerance profile, including the impact on quality of life, with a particular focus on the frailest subgroups, and to attempt to define the optimal treatment strategy for elderly and fragile patients (dosage and therapeutic sequence). Background: Breast cancer (BC) incidence increases with age, particularly in HR-positive/HER2-negative subtypes. Cyclin-dependent kinase 4 and 6 inhibitors (CDK 4/6is) alongside endocrine therapy (ET) have emerged as promising treatments for HR-positive/HER2-negative advanced and early BC. However, their efficacy, safety, and impact on quality of life (QoL) in older and frail patients remain underexplored. Methods: This position paper assesses the existing literature from 2015 to 2024, focusing on CDK4/6is use in patients aged 65 years and older with HR-positive/HER2-negative BC. Results: Our analysis methodically addresses critical questions regarding the utilization of CDK4/6is in the elderly BC patient population, organizing findings from the metastatic and adjuvant settings. In the metastatic setting, CDK4/6is significantly improve progression-free survival (PFS), paralleling benefits observed in younger patients, and suggest potential overall survival (OS) benefits, warranting further investigation. Despite an increased incidence of grade ≥ 3 adverse events (AEs), such as neutropenia and asthenia, CDK4/6is present a markedly lower toxicity profile compared to traditional chemotherapy, with manageable side effects. QoL analysis indicates that integrating CDK4/6is into treatment regimens does not significantly impact elderly BC patients' daily life and symptom management. Special attention is given to frail subgroups, and personalized approaches are recommended to balance efficacy and adverse effects, such as starting with ET alone and introducing CDK4/6is upon progression in patients with a low disease burden. Transitioning to the adjuvant setting, early results, particularly with abemaciclib, indicate positive effects on disease-free survival (DFS), emphasizing the need for continued analysis to validate these findings and assess long-term implications. However, data on older patients are insufficient to conclude whether they truly benefit from this treatment. Conclusion: Overall, CDK4/6is present a favorable benefit-risk profile in older BC patients, at least in advanced BC; however, further research is warranted to optimize treatment strategies and improve outcomes in this population [ABSTRACT FROM AUTHOR]

Simple Summary: Triple negative breast cancer (TNBC) comprises 10–20% of diagnosed breast cancers. TNBCs are devoid of common biomarkers such as an estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Research is currently being conducted to determine the androgen receptor's (AR) role in TNBC and determine its ability to be utilized as an effective drug target in the absence of the commonly targeted receptors. Many studies combine anti-androgen drugs with other chemotherapy to decrease tumor growth and proliferation. The further understanding of AR's mechanism in tumor cells can improve drug efficacy as well as the prognoses of patients suffering from TNBC. To assess AR's role in TNBC treatment, various existing and completed clinical trials targeting AR or co-targeting AR with other pertinent signaling molecules were analyzed. Cyclin-dependent kinase 4/6 (CDK4/6), cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17 lyase), and the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway were some of the most prevalent biomarkers used in combination therapy with AR inhibitors in these trials. Studying how AR functions in tandem with these molecules can have increasing breakthroughs in the treatment options for TNBC. Previous studies have been largely unsuccessful in utilizing AR as the sole drug target for systemic targeted treatment in TNBC. However, there is a lack of other commonly used drug target biomarkers in the treatment of this disease, as well. Thus, analyzing the clinical benefit rate (CBR) within clinical trials that use combination therapy can prove to be imperative to the progression of improving treatment options and prognoses. [ABSTRACT FROM AUTHOR]

Simple Summary: Internationally, in women, breast cancer (BC) is the most common cancer type and is the leading cause of cancer-related death. There are two main histological classifications of BC, carcinoma in situ and carcinoma invasive. BC is further histologically subclassified as ductal carcinomas and lobular carcinomas. Once diagnosed, BC is typically treated based on the molecular subtype of cancer. The subtypes are based on the presence or absence of hormone receptors progesterone receptor (PR), estrogen receptor (ER), and human epidermal growth factor receptor 2 (HER2). The main molecular subtypes of BC include Luminal A (ER+, PR+, HER2-), Luminal B (ER+, PR+ HER2+), HER2 enriched (ER−, PR−, HER2+), and basal-like/ triple-negative BC (TNBC). People with hormone-positive (ER+ and or HER2+) BC are typically treated with endocrine therapy and chemotherapy, making them easier to treat. TNBC, on the other hand, is more challenging to treat due to the lack of hormone receptors and the aggressiveness of this form of cancer. Unfortunately, most therapies used to treat BC can often lead to drug resistance, relapse, and metastasis to other body parts. Due to its complexity and many mechanisms, it is difficult to overcome drug resistance. However, further research into potential drug targets and their relationship with drug resistance could help circumvent BC drug resistance. Breast cancer is the most common cause of cancer-related death in women worldwide. Multidrug resistance (MDR) has been a large hurdle in reducing BC death rates. The drug resistance mechanisms include increased drug efflux, enhanced DNA repair, senescence escape, epigenetic alterations, tumor heterogeneity, tumor microenvironment (TME), and the epithelial-to-mesenchymal transition (EMT), which make it challenging to overcome. This review aims to explain the mechanisms of resistance in BC further, identify viable drug targets, and elucidate how those targets relate to the progression of BC and drug resistance. [ABSTRACT FROM AUTHOR]

Simple Summary: Solid tumors account for ~60% of pediatric, as well as adolescent and young adult (AYA), cancers, and outcomes for patients with these progressive diseases remain poor. This highlights the critical need to develop tumor models from patients with aggressive cancers so that oncogenic signatures can be identified for therapeutic testing. Thus, patient-derived xenografts (PDXs) were established from sarcoma and Wilms tumor patients at diagnosis or following treatment. Overall, the molecular landscape of serially passaged PDXs recapitulated the original tumor based on an integrated multi-OMICS pipeline that cross-validated cancer-associated pathways. Actionable mechanisms of tumor progression were identified. CDK4/6 and BETs were prioritized as biomarkers of therapeutic response for in vivo validation. In osteosarcoma PDXs harboring pertinent molecular signatures, inhibition of CDK4/6 or BETs decreased growth. This systematic approach that links patient disease history to data generated from its corresponding PDX provides a foundation to discover improved therapies for patients with high-risk cancers. Establishment of clinically annotated, molecularly characterized, patient-derived xenografts (PDXs) from treatment-naïve and pretreated patients provides a platform to test precision genomics-guided therapies. An integrated multi-OMICS pipeline was developed to identify cancer-associated pathways and evaluate stability of molecular signatures in a panel of pediatric and AYA PDXs following serial passaging in mice. Original solid tumor samples and their corresponding PDXs were evaluated by whole-genome sequencing, RNA-seq, immunoblotting, pathway enrichment analyses, and the drug–gene interaction database to identify as well as cross-validate actionable targets in patients with sarcomas or Wilms tumors. While some divergence between original tumor and the respective PDX was evident, majority of alterations were not functionally impactful, and oncogenic pathway activation was maintained following serial passaging. CDK4/6 and BETs were prioritized as biomarkers of therapeutic response in osteosarcoma PDXs with pertinent molecular signatures. Inhibition of CDK4/6 or BETs decreased osteosarcoma PDX growth (two-way ANOVA, p < 0.05) confirming mechanistic involvement in growth. Linking patient treatment history with molecular and efficacy data in PDX will provide a strong rationale for targeted therapy and improve our understanding of which therapy is most beneficial in patients at diagnosis and in those already exposed to therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: This review aims to provide an outline of the potential use of plant-based foods, nutraceuticals, and derived micronutrients—particularly those typically found in the Mediterranean diet—as anticancer agents, with a focus on their mechanism of action as cyclin-dependent kinase inhibitors (CDKIs) by inactivating the CDK 4/6 pathway and the regulation of the cell-cycle cascade. We discuss the preclinical and pharmacological significance of some already approved CDK blockers as a promising therapeutic approach against breast and ovarian cancers. Overweight and obesity constitute the most impactful lifestyle-dependent risk factors for cancer and have been tightly linked to a higher number of tumor-related deaths nowadays. The excessive accumulation of energy can lead to an imbalance in the level of essential cellular biomolecules that may result in inflammation and cell-cycle dysregulation. Nutritional strategies and phytochemicals are gaining interest in the management of obesity-related cancers, with several ongoing and completed clinical studies that support their effectiveness. At the same time, cyclin-dependent kinases (CDKs) are becoming an important target in breast and ovarian cancer treatment, with various FDA-approved CDK4/6 inhibitors that have recently received more attention for their potential role in diet-induced obesity (DIO). Here we provide an overview of the most recent studies involving nutraceuticals and other dietary strategies affecting cell-cycle pathways, which might impact the management of breast and ovarian cancers, as well as the repurposing of already commercialized chemotherapeutic options to treat DIO. [ABSTRACT FROM AUTHOR]

Establishment of clinically annotated, molecularly characterized, patient-derived xenografts (PDXs) from treatment-naïve and pretreated patients provides a platform to test precision genomics-guided therapies. An integrated multi-OMICS pipeline was developed to identify cancer-associated pathways and evaluate stability of molecular signatures in a panel of pediatric and AYA PDXs following serial passaging in mice. Original solid tumor samples and their corresponding PDXs were evaluated by whole-genome sequencing, RNA-seq, immunoblotting, pathway enrichment analyses, and the drug−gene interaction database to identify as well as cross-validate actionable targets in patients with sarcomas or Wilms tumors. While some divergence between original tumor and the respective PDX was evident, majority of alterations were not functionally impactful, and oncogenic pathway activation was maintained following serial passaging. CDK4/6 and BETs were prioritized as biomarkers of therapeutic response in osteosarcoma PDXs with pertinent molecular signatures. Inhibition of CDK4/6 or BETs decreased osteosarcoma PDX growth (two-way ANOVA, p < 0.05) confirming mechanistic involvement in growth. Linking patient treatment history with molecular and efficacy data in PDX will provide a strong rationale for targeted therapy and improve our understanding of which therapy is most beneficial in patients at diagnosis and in those already exposed to therapy.

Simple Summary: Cyclin-dependent kinase (CDK) 4/6 inhibitors, in combination with endocrine therapies, are now the standard of care for patients with metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer. Despite the effectiveness of CDK4/6 inhibitors, acquired resistance occurs in almost all cases. We developed and used a palbociclib-resistant preclinical model and studied the overcoming strategies, using FDA-approved chemotherapy in combination with a CDK4/6 inhibitor. We demonstrated that sequential abemaciclib treatment following eribulin-enhanced anti-tumor activity in vitro and in vivo on the CDK4/6 inhibitor-resistant cells by more effectively inhibiting the G2/M cell cycle phase. The sequential combination of abemaciclib following eribulin could be an effective treatment strategy in overcoming resistance to CDK4/6 inhibitors in HR-positive breast cancer. Breast cancer remains a leading cancer burden among women worldwide. Acquired resistance of cyclin-dependent kinase (CDK) 4/6 inhibitors occurs in almost all hormone receptor (HR)-positive subtype cases, comprising 70% of breast cancers, although CDK4/6 inhibitors combined with endocrine therapy are highly effective. CDK4/6 inhibitors are not expected to cooperate with cytotoxic chemotherapy based on the basic cytotoxic chemotherapy mode of action that inhibits rapidly proliferating cells. The palbociclib-resistant preclinical model developed in the current study investigated whether the combination of abemaciclib, CDK4/6 inhibitor with eribulin, an antimitotic chemotherapy could be a strategy to overcome palbociclib-resistant HR-positive breast cancer. The current study demonstrated that sequential abemaciclib treatment following eribulin synergistically suppressed CDK4/6 inhibitor-resistant cells by inhibiting the G2/M cell cycle phase more effectively. The current study showed the significant association of the pole-like kinase 1 (PLK1) level and palbociclib resistance. Moreover, the cumulative PLK1 inhibition in the G2/M phase by each eribulin or abemaciclib proved to be a mechanism of the synergistic effect. The synergistic antitumor effect was also supported by in vivo study. The sequential combination of abemaciclib following eribulin merits further clinical trials to overcome resistance to CDK4/6 inhibitors in HR-positive breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Systemic treatment options for advanced neuroendocrine tumors have significantly been improved in the last decade. However efficacy of systemic therapy is limited by tumor resistance and therefore there is a need for further treatment options. Inhibition of the Ras-Raf-Mek-Erk signaling cascade might be a promising new treatment strategy in neuroendocrine neoplasms. In this study we investigated the effects of the MEK inhibitor trametinib, the ERK inhibitor SCH772984 and the CDK4/6 inhibitor ribociclib in human neuroendocrine tumor cell lines BON1, QGP1 and NCI-H727 in vitro. Trametinib alone and in synergism with ribociclib demonstrated antiproliferative effects. Combination therapy of MEK inhibitors and CDK4/6 inhibitors might be a potential strategy to overcome CDK4/6 inhibitor resistance in neuroendocrine tumors. Objectives: This study assessed the antitumoral activity of the MEK inhibitor trametinib (TMT212) and the ERK1/2 inhibitor SCH772984, alone and in combination with the CDK4/6 inhibitor ribociclib (LEE011) in human neuroendocrine tumor (NET) cell lines in vitro. Methods: Human NET cell lines BON1, QGP-1, and NCI-H727 were treated with trametinib or SCH772984, alone and in combination with ribociclib, to assess cell proliferation, cell cycle distribution, and protein signaling using cell proliferation, flow cytometry, and Western blot assays, respectively. Results: Trametinib and SCH772984, alone and in combination with ribociclib, significantly reduced NET cell viability and arrested NET cells at the G1 phase of the cell cycle in all three cell lines tested. In addition, trametinib also caused subG1 events and apoptotic PARP cleavage in QGP1 and NCI-H727 cells. A western blot analysis demonstrated the use of trametinib alone and trametinib in combination with ribociclib to decrease the expression of pERK, cMyc, Chk1, pChk2, pCDK1, CyclinD1, and c-myc in a time-dependent manner in NCI-H727 and QGP-1 cells. Conclusions: MEK and ERK inhibition causes antiproliferative effects in human NET cell lines in vitro. The combination of the MEK inhibitor trametinib (TMT212) with the CDK4/6 inhibitor ribociclib (LEE011) causes additive antiproliferative effects. Future preclinical and clinical studies of MEK inhibition in NETs should be performed. [ABSTRACT FROM AUTHOR]

Simple Summary: We previously showed that ribociclib induces cell cycle arrest in some human papillomavirus (HPV)-negative squamous cell carcinomas of the head and neck (SCCHN) models. However, in vivo, ribociclib has only a cytostatic effect, suggesting that its activity needs to be optimized in combination with other treatments. We investigated the activity of ribociclib in combination with cetuximab in several HPV-negative SCCHN patient-derived tumor xenograft (PDTX) models. We found that the combination of cetuximab and ribociclib was not significantly more active than cetuximab monotherapy. In addition, our observations also suggest that the combination of cetuximab with a cyclin-dependent kinase (CDK) 4/6 inhibitor may reduce the activity of the CDK4/6 inhibitor in some cetuximab-resistant models. Our work has significant clinical implications since combinations of anti-epidermal growth factor receptor (EGFR) therapy and CDK4/6 inhibitors are currently being investigated in clinical trials. Epidermal growth factor receptor (EGFR) overexpression is observed in 90% of human papillomavirus (HPV)-negative squamous cell carcinomas of the head and neck (SCCHN). Cell cycle pathway impairments resulting in cyclin-dependent kinase (CDK) 4 and 6 activation, are frequently observed in SCCHN. We investigated the efficacy of ribociclib, a CDK4/6 inhibitor, in combination with cetuximab, a monoclonal antibody targeting the EGFR, in HPV-negative SCCHN patient-derived tumor xenograft (PDTX) models. The combination of cetuximab and ribociclib was not significantly more active than cetuximab monotherapy in all models investigated. In addition, the combination of cetuximab and ribociclib was less active than ribociclib monotherapy in the cetuximab-resistant PDTX models. In these models, a significant downregulation of the retinoblastoma (Rb) protein was observed in cetuximab-treated mice. We also observed Rb downregulation in the SCCHN cell lines chronically exposed and resistant to cetuximab. In addition, Rb downregulation induced interleukin 6 (Il-6) secretion and the Janus kinase family member/signal transducer and activator of transcription (JAK/STAT) pathway activation that might be implicated in the cetuximab resistance of these cell lines. To conclude, cetuximab is not an appropriate partner for ribociclib in cetuximab-resistant SCCHN models. Our work has significant clinical implications since the combination of anti-EGFR therapy with CDK4/6 inhibitors is currently being investigated in clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are widely used to treat metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer. Despite the effectiveness of CDK4/6 inhibitors, acquired resistance occurs in almost all cases. Strategies to address this issue have not been developed yet. We investigated mechanisms of resistance to CDK4/6 inhibitor in breast cancer and potential therapeutic strategies. We found that cyclin E-CDK2 mediated phosphorylation of C-MYC is responsible for resistance to CDK4/6 inhibitor by suppressing C-MYC induced senescence. On the contrary, the synergistic anti-proliferative effect of the combined inhibition of CDK2 and CDK4/6 overcomes acquired resistance to CDK4/6 inhibitors by enhancing senescence. Our findings could pave the way for the development CDK2-specific kinase inhibitor for the treatment of breast cancers that are resistant to CDK4/6 inhibitor. Breast cancer represents the number one global cancer burden in women and the hormone receptor (HR)-positive subtype comprises approximately 70% of breast cancers. Unfortunately, acquired resistance ultimately occurs in almost all cases, even though cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are a highly effective therapy for HR-positive/human epidermal growth factor receptor 2-negative subtype. Here, we investigated mechanisms of resistance to CDK4/6 inhibitor and potential therapeutic strategies using our palbociclib-resistant preclinical model. We observed that cyclin E was significantly overexpressed in palbociclib-resistant cells, and similar association was also confirmed in pleural effusion samples collected from HR-positive breast cancer patients. After confirmation of cyclin E-CDK2 interaction by co-immunoprecipitation, we demonstrated CDK2 inhibition combined with palbociclib synergistically suppressed proliferation of palbociclib-resistant cells and growth of palbociclib-resistant xenograft in mice. We also proved that enhancing C-MYC-mediated senescence is a novel mechanism behind the synergism created by targeting both CDK2 and CDK4/6. Furthermore, the clinical relevance of cyclin E as a therapeutic target was supported by significant association between CCNE1 overexpression and poor prognosis based on large-scale public gene expression data sets in HR-positive breast cancer patients. Therefore, we propose cyclin E-CDK2 signaling as a promising therapeutic target for overcoming cyclin E-associated resistance to CDK4/6 inhibitor. [ABSTRACT FROM AUTHOR]

Sterile alpha motif and histidine-aspartic acid domain-containing protein 1 (SAMHD1) is a dNTP triphosphohydrolase involved in the regulation of the intracellular dNTP pool, linked to viral restriction, cancer development and autoimmune disorders. SAMHD1 function is regulated by phosphorylation through a mechanism controlled by cyclin-dependent kinases and tightly linked to cell cycle progression. Recently, SAMHD1 has been shown to decrease the efficacy of nucleotide analogs used as chemotherapeutic drugs. Here, we demonstrate that SAMHD1 can enhance or decrease the efficacy of various classes of anticancer drug, including nucleotide analogues, but also anti-folate drugs and CDK inhibitors. Importantly, we show that selective CDK4/6 inhibitors are pharmacological activators of SAMHD1 that act by inhibiting its inactivation by phosphorylation. Combinations of a CDK4/6 inhibitor with nucleoside or folate antimetabolites potently enhanced drug efficacy, resulting in highly synergic drug combinations (CI < 0.04). Mechanistic analyses reveal that cell cycle-controlled modulation of SAMHD1 function is the central process explaining changes in anticancer drug efficacy, therefore providing functional proof of the potential of CDK4/6 inhibitors as a new class of adjuvants to boost chemotherapeutic regimens. The evaluation of SAMHD1 expression in cancer tissues allowed for the identification of cancer types that would benefit from the pharmacological modulation of SAMHD1 function. In conclusion, these results indicate that the modulation of SAMHD1 function may represent a promising strategy for the improvement of current antimetabolite-based treatments. [ABSTRACT FROM AUTHOR]

While clinical responses to palbociclib have been promising, metastatic breast cancer remains incurable due to the development of resistance. We generated estrogen receptor-positive (ER+) and ER-negative (ER−) cell line models and determined their permissiveness and cellular responses to an oncolytic adenovirus (OAd) known as Ad5/3-delta24. Analysis of ER+ and ER− palbociclib-resistant cells revealed two clearly distinguishable responses to the OAd. While ER+ palbociclib-resistant cells displayed a hypersensitive phenotype to the effects of the OAd, ER− palbociclib-resistant cells showed a resistant phenotype to the OAd. Hypersensitivity to the OAd in ER+ palbociclib-resistant cells correlated with a decrease in type I interferon (IFN) signaling, an increase in viral entry receptor expression, and an increase in cyclin E expression. OAd resistance in ER− palbociclib-resistant cells correlated with an increase in type I IFN signaling and a marked decrease in viral entry receptor. Using the OAd as monotherapy caused significant cytotoxicity to both ER+ and ER− palbociclib-sensitive cell lines. However, the addition of palbociclib increased the oncolytic activity of the OAd only in ER+ palbociclib-sensitive cells. Our studies provide a mechanistic base for a novel anti-cancer regimen composed of an OAd in combination with palbociclib for the treatment of ER+ breast cancer. [ABSTRACT FROM AUTHOR]