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IntroductionConventional regimens for head and neck squamous cell carcinoma (HNSCC) are limited in efficacy and are associated with adverse toxicities. Food and Drug Administration (FDA) approved molecular targeting agents include the HER1 (EGFR)-directed monoclonal antibody cetuximab and the immune checkpoint inhibitors nivolumab and pembrolizumab. However, clinical benefit is only seen in roughly 15-20% of HNSCC patients treated with these agents. New molecular targeting agents are needed that either act with monotherapeutic activity against HNSCC tumors or enhance the activities of current therapies, particularly immunotherapy. Small-molecule tyrosine kinase inhibitors (TKIs) represent a viable option toward this goal.Areas coveredThis review provides an update on TKIs currently under investigation in HNSCC. We focus our review on data obtained and trials underway in HNSCC, including salivary gland cancers and nasopharyngeal carcinomas, but excluding thyroid cancer and esophageal cancer.Expert opinionWhile some emerging TKIs have shown clinical benefit, the positive effects have, largely, been modest. The design of clinical trials of TKIs has been hampered by a lack of understanding of biomarkers that can be used to define patient populations most likely to respond. Further preclinical and translational studies to define biomarkers of TKI response will be critically important.

Molecularly targeted cancer therapy has improved outcomes for patients with cancer with targetable oncoproteins, such as mutant EGFR in lung cancer. Yet, the long-term survival of these patients remains limited, because treatment responses are typically incomplete. One potential explanation for the lack of complete and durable responses is that oncogene-driven cancers with activating mutations of EGFR often harbor additional co-occurring genetic alterations. This hypothesis remains untested for most genetic alterations that co-occur with mutant EGFR. Here, we report the functional impact of inactivating genetic alterations of the mRNA splicing factor RNA-binding motif 10 (RBM10) that co-occur with mutant EGFR. RBM10 deficiency decreased EGFR inhibitor efficacy in patient-derived EGFR-mutant tumor models. RBM10 modulated mRNA alternative splicing of the mitochondrial apoptotic regulator Bcl-x to regulate tumor cell apoptosis during treatment. Genetic inactivation of RBM10 diminished EGFR inhibitor-mediated apoptosis by decreasing the ratio of (proapoptotic) Bcl-xS to (antiapoptotic) Bcl-xL isoforms of Bcl-x. RBM10 deficiency was a biomarker of poor response to EGFR inhibitor treatment in clinical samples. Coinhibition of Bcl-xL and mutant EGFR overcame the resistance induced by RBM10 deficiency. This study sheds light on the role of co-occurring genetic alterations and on the effect of splicing factor deficiency on the modulation of sensitivity to targeted kinase inhibitor cancer therapy.

INTRODUCTION: Immune checkpoint inhibitor (ICI) therapy has been found to increase the risk/severity of immune-mediated adverse events with subsequent kinase inhibitor treatment in oncogenically driven cancers. We explored the risk for hypersensitivity with selpercatinib, a first-in-class highly selective and potent, central nervous system-active RET inhibitor, in prior ICI-treated patients with RET fusion-positive NSCLC compared with their ICI-naive counterparts. METHODS: Data from patients enrolled by December 16, 2019, in the ongoing phase 1/2 LIBRETTO-001 (NCT03157128) trial were analyzed for hypersensitivity reactions reported using preferred terms of hypersensitivity/drug hypersensitivity and defined as a constellation of symptoms/findings characterized by maculopapular rash, often preceded by fever with arthralgias/myalgias, followed by greater than or equal to 1 of the following signs/symptoms: thrombocytopenia, increased aspartate aminotransferase or alanine aminotransferase, hypotension, tachycardia, or increased creatinine. RESULTS: Of 329 patients, 22 (7%) who experienced a grade 1 to 3 hypersensitivity reaction that met the defined constellation of events were attributed to selpercatinib by investigators, and more often in prior ICI-treated (n = 17, 77%) than ICI-naive (n = 5, 23%) patients. There were 19 patients with selpercatinib-related hypersensitivity who resumed selpercatinib post-hypersensitivity with dose modification/supportive care. Furthermore, 17 patients, of whom 14 received prior ICI therapy, were still on treatment at twice daily doses of 40 mg (n = 5), 80 mg (n = 4), 120 mg (n = 4), and 160 mg (n = 4). CONCLUSIONS: Rates of selpercatinib-related hypersensitivity were low overall and, as with other kinase inhibitors, occurred predominantly in prior ICI-treated patients. Hypersensitivity to selpercatinib can be managed with supportive care measures regardless of prior ICI status and is reversible.

Semi-rational enzyme engineering is a powerful method to develop industrial biocatalysts. Profiting from advances in molecular biology and bioinformatics, semi-rational approaches can effectively accelerate enzyme engineering campaigns. Here, we present the optimization of a ketoreductase from Sporidiobolus salmonicolor for the chemo-enzymatic synthesis of ipatasertib, a potent protein kinase B inhibitor. Harnessing the power of mutational scanning and structure-guided rational design, we created a 10-amino acid substituted variant exhibiting a 64-fold higher apparent kcat and improved robustness under process conditions compared to the wild-type enzyme. In addition, the benefit of algorithm-aided enzyme engineering was studied to derive correlations in protein sequence-function data, and it was found that the applied Gaussian processes allowed us to reduce enzyme library size. The final scalable and high performing biocatalytic process yielded the alcohol intermediate with ≥ 98% conversion and a diastereomeric excess of 99.7% (R,R-trans) from 100 g L−1 ketone after 30 h. Modelling and kinetic studies shed light on the mechanistic factors governing the improved reaction outcome, with mutations T134V, A238K, M242W and Q245S exerting the most beneficial effect on reduction activity towards the target ketone. Ipatasertib is a potent Akt (protein kinase B) inhibitor synthesized via a chemoenzymatic process. Here, the authors use mutational scanning and algorithm-aided enzyme engineering to optimize a ketoreductase from Sporidiobolus salmonicolor and generate a 10-amino acid substituted variant exhibiting a 64-fold higher kcat and improved yield for the relevant alcohol intermediate, with ≥ 98% conversion and a diastereomeric excess of 99.7% (R,R-trans) from 100 g L−1 ketone after 30 h. [ABSTRACT FROM AUTHOR]

Background: Targeting receptor-interacting serine/threonine protein kinase 1 could mitigate the devastating sequelae of the hyperinflammatory state observed in severe cases of COVID-19. This study explored the immunomodulatory and clinical effects of the receptor-interacting serine/threonine protein kinase 1 inhibitor SAR443122 (eclitasertib) in patients with severe COVID-19. Methods: In this Phase 1b, double-blinded, placebo-controlled study (NCT04469621) a total of 82 patients were screened, of whom 68 patients were eligible and randomized (2:1) to receive eclitasertib 600 mg (300 mg twice daily) or placebo up to 14 days. Primary outcome was relative change in C-reactive protein from baseline to Day 7. Time to clinical improvement using 7-point ordinal scale, ventilator/respiratory failure-free days, change in SpO2/FiO2 ratio, and biomarkers of severe COVID-19 were explored. Results: Geometric mean ratio (point estimate [90% confidence interval]) of the relative change from baseline in C-reactive protein with eclitasertib vs. placebo on Day 7 was 0.85 (0.49–1.45; p = 0.30). Median time to 50% decrease in C-reactive protein from baseline was 3 days vs. 5 days (p = 0.056) with eclitasertib vs. placebo. Median time to ≥ 2-point improvement on 7-point clinical symptoms scale was 8 days vs. 10 days with eclitasertib vs. placebo (p = 0.38). Mean ventilator/respiratory failure-free days, change in baseline-adjusted SpO2/FiO2 ratio, and clinical biomarkers showed consistent numerical improvements with eclitasertib vs. placebo. The most frequently reported treatment-emergent adverse events were gastrointestinal disorders and condition aggravated/worsened COVID-19 pneumonia. Conclusions: Eclitasertib was well tolerated with consistent trends toward more rapid resolution of inflammatory biomarkers and clinical improvement in severe COVID-19 patients than placebo. ClinicalTrials.gov identifier: NCT04469621, first posted on clinicaltrials.gov on July 14, 2020. [ABSTRACT FROM AUTHOR]

Background: Anaplastic thyroid cancer (ATC) is a rare and aggressive neoplasm. We still lack effective treatment options, so survival rates remain very low. Here, we aimed to evaluate the activity of the combination of lenvatinib and pembrolizumab as systemic first-line therapy in ATC. Methods: In a retrospective analysis, we investigated the activity and tolerability of combined lenvatinib (starting dose 14 to 24 mg daily) and pembrolizumab (200 mg every three weeks) as first-line therapy in an institutional cohort of ATC patients. Results: Five patients with metastatic ATC received lenvatinib and pembrolizumab as systemic first-line therapy. The median progression-free survival was 4.7 (range 0.8–5.9) months, and the median overall survival was 6.3 (range 0.8-not reached) months. At the first follow-up, one patient had partial response, three patients had stable disease, and one patient was formally not evaluable due to interference of assessment by concomitant acute infectious thyroiditis. This patient was then stable for more than one year and was still on therapy at the data cutoff without disease progression. Further analyses revealed deficient DNA mismatch repair, high CD8+ lymphocyte infiltration, and low macrophage infiltration in this patient. Of the other patients, two had progressive disease after adverse drug reactions and therapy de-escalation, and two died after the first staging. For all patients, the PD-L1 combined positive score ranged from 12 to 100%. Conclusions: The combination of lenvatinib and pembrolizumab was effective and moderately tolerated in treatment-naïve ATC patients with occasional long-lasting response. However, we could not confirm the exceptional responses for this combination therapy reported before in pretreated patients. [ABSTRACT FROM AUTHOR]

Cancer is a complicated, multifaceted disease that can impact any organ in the body. Various chemotherapeutic agents have a low selectivity and are very toxic when used alone or in combination with others. Resistance is one of the most important hurdles that develop due to the use of many anticancer therapeutics. As a result, treating cancer requires a target-specific palliative care strategy. Remarkable scientific discoveries have shed light on several of the molecular mechanisms underlying cancer, resulting in the development of various targeted anticancer agents. One of the most important heterocyclic motifs is quinazoline, which has a wide range of biological uses and chemical reactivities. Newer, more sophisticated medications with quinazoline structures have been found in the last few years, and great strides have been made in creating effective protocols for building these pharmacologically active scaffolds. A new class of chemotherapeutic agents known as quinazoline-based derivatives possessing anticancer properties consists of several well-known compounds that block different protein kinases and other molecular targets. This review highlights recent updates (2021–2024) on various quinazoline-based derivatives acting against different protein kinases as anticancer chemotherapeutics. It also provides guidance for the design and synthesis of novel quinazoline analogues that could serve as lead compounds. [ABSTRACT FROM AUTHOR]

High-dose irradiation can trigger numerous endothelial dysfunctions, including apoptosis, the overexpression of adhesion molecules, and alteration of adherens junctions. Altogether, these endothelial dysfunctions contribute to the development of tissue inflammation and organ damage. The development of endothelial dysfunctions may depend on protein phosphorylation by various protein kinases, but the possible role of protein kinase A (PKA) has not been investigated so far, and efficient compounds able to protect the endothelium from irradiation effects are needed. Here we report the beneficial effects of the PKA inhibitor KT5720 on a panel of irradiation-induced endothelial dysfunctions in human pulmonary microvascular endothelial cells (HPMECs). High-dose X-irradiation (15 Gy) triggered the late apoptosis of HPMECs independent of the ceramide/P38 MAP kinase pathway or p53. In contrast, the treatment of HPMECs with KT5720 completely prevented irradiation-induced apoptosis, whether applied before or after cell irradiation. Immunostainings of irradiated monolayers revealed that KT5720 treatment preserved the overall integrity of endothelial monolayers and adherens junctions linking endothelial cells. Real-time impedance measurements performed in HPMEC monolayers confirmed the overall protective role of KT5720 against irradiation. Treatment with KT5720 before or after irradiation also reduced irradiation-induced ICAM-1 overexpression. Finally, the possible role for PKA in the development of endothelial dysfunctions is discussed, but the potency of KT5720 to inhibit the development of a panel of irradiation-induced endothelial dysfunctions, whether applied before or after irradiation, suggests that this compound could be of great interest for both the prevention and treatment of vascular damages in the event of exposure to a high dose of radiation. [ABSTRACT FROM AUTHOR]

This document discusses the resurgence of covalent inhibitors in drug discovery and chemical biology. Covalent inhibitors, which form a covalent bond with their target proteins, have historically been avoided due to concerns about safety. However, recent advancements have shown that these inhibitors can be effective and safe. The document highlights various aspects of covalent inhibitors, including their design, mechanisms of action, and applications in different fields. It also includes research papers and reviews from experts in the field, covering topics such as the development of covalent inhibitors for specific diseases and the detection of covalent protein-drug adducts. Overall, this document provides a comprehensive overview of the current state of covalent inhibitor research. [Extracted from the article]

Simple Summary: The estrogen receptor (ER) plays a critical role in the initiation and progression of breast cancer. Utilizing specialized therapies aimed at the ER has been effective in many instances and is commonly employed in breast cancer treatment protocols. The selection of therapy depends on multiple factors, including the menopausal status, breast cancer stage, and unique tumor attributes. These therapies can function independently as monotherapy, or in conjunction or sequential alignment with other treatments, based on the distinct characteristics of the breast cancer and the patient's overall health. Furthermore, current research endeavors are focused on producing newer and more precise therapies for breast cancer, which include strategies to combat resistance mechanisms. The objective of this review is to provide a snapshot of the existing landscape and sketch out future paths for the progression of HR+ breast cancer treatments currently under clinical development. The hormone receptor-positive (HR+) type is the most frequently identified subtype of breast cancer. HR+ breast cancer has a more positive prognosis when compared to other subtypes, such as human epidermal growth factor protein 2-positive disorder and triple-negative disease. The advancement in treatment outcomes for advanced HR+ breast cancer has been considerably elevated due to the discovery of cyclin-dependent kinase 4/6 inhibitors and their combination effects with endocrine therapy. However, despite the considerable effectiveness of tamoxifen, a selective estrogen receptor modulator (SERMs), and aromatase inhibitors (AI), the issue of treatment resistance still presents a significant challenge for HR+ breast cancer. As a result, there is a focus on exploring new therapeutic strategies such as targeted protein degradation and covalent inhibition for targeting ERα. This article discusses the latest progress in treatments like oral selective ER degraders (SERDs), complete estrogen receptor antagonists (CERANs), selective estrogen receptor covalent antagonists (SERCAs), proteolysis targeting chimera (PROTAC) degraders, and combinations of CDK4/6 inhibitors with endocrine therapy. The focus is specifically on those compounds that have transitioned into phases of clinical development. [ABSTRACT FROM AUTHOR]

Simple Summary: PIM3 is a serine/threonine kinase linked to various oncogenic processes and often overexpressed in solid cancers such as pancreatic, liver, colon, stomach, and breast cancers. Upregulation of PIM3 is associated with poor patient prognosis, and its inhibition leads to reduced cell proliferation, invasion, and in vivo tumor growth; thus, PIM3 represents an emerging novel therapeutic target in cancer. Although pan-PIM inhibitors have entered clinical trials in hematological cancers, they were not potent or specific enough or exhibited side effects; thus, currently, there is no FDA-approved inhibitor for targeting all PIMs or PIM3. The development of selective and effective PIM3 inhibitors may have a significant clinical impact and a novel potential therapeutic strategy for PIM3-driven solid and hematological cancers. PIM3 (provirus-integrating Moloney site 3) is a serine/threonine kinase and belongs to the PIM family (PIM1, PIM2, and PIM3). PIM3 is a proto-oncogene that is frequently overexpressed in cancers originating from endoderm-derived tissues, such as the liver, pancreas, colon, stomach, prostate, and breast cancer. PIM3 plays a critical role in activating multiple oncogenic signaling pathways promoting cancer cell proliferation, survival, invasion, tumor growth, metastasis, and progression, as well as chemo- and radiation therapy resistance and immunosuppressive microenvironment. Genetic inhibition of PIM3 expression suppresses in vitro cell proliferation and in vivo tumor growth and metastasis in mice with solid cancers, indicating that PIM3 is a potential therapeutic target. Although several pan-PIM inhibitors entered phase I clinical trials in hematological cancers, there are currently no FDA-approved inhibitors for the treatment of patients. This review provides an overview of recent developments and insights into the role of PIM3 in various cancers and its potential as a novel molecular target for cancer therapy. We also discuss the current status of PIM-targeted therapies in clinical trials. [ABSTRACT FROM AUTHOR]

Purpose: Endothelial keratoplasty (EK) is the conventional treatment to improve visual acuity of corneal endothelium decompensation (CED) patients, with other therapies mainly for symptomatic relief. However, the shortage of corneal grafts and other limitations to EK urge the development of novel alternative treatments. In the last decade, novel options have been proposed, yet only a limited number of reviews have systematically reported on outcomes. Therefore, this systematic review evaluates the existing clinical evidence of novel surgical approaches for CED. Method: We identified 24 studies that illustrated the clinical observations of the surgical approaches in interest. We included Descemet stripping only (DSO), Descemet membrane transplantation (DMT) where Descement membrane alone instead of corneal endothelium with cells is transplanted, and cell-based therapy. Results: In general, these therapies may provide visual outcomes comparable with EK under specific conditions. DSO and DMT target CED with relatively healthy peripheral corneal endothelium like Fuchs' corneal endothelial dystrophy, while cell-based therapy offers more versatile applications. Side effects of DSO would decrease with modifications to surgical techniques. Moreover, Rho-associated protein kinase inhibitor adjuvant therapy could enhance clinical results in DSO and cell-based therapy. Conclusion: Long-term controlled clinical trials with larger sample size on the therapies are needed. The simplicity of DSO and the high translational potential of cell-based therapy to treat CED of most etiologies made these two treatment strategies promising. [ABSTRACT FROM AUTHOR]

Summary: This study aimed to prepare SLC7A5 transporters targeted liposomes of Ribociclib (RB) by stear(o)yl conjugation of Phe, Asp, Glu amino acids to liposomes as targeting moieties. The liposomes were optimized for their formulations. Cell analysis on two cell lines of MCF-7 and NIH-3T3 were done including; cell viability test by MTT assay, cellular uptake, and cell cycle arrest by flow cytometry. The optimal liposomes showed the particle size of 123.6 ± 1.3 nm, drug loading efficiency and release efficiency of 83.87% ± 1.33% and 60.55% ± 0.46%, respectively. The RB loaded liposomes showed no hemolysis activity. Targeted liposomes increased cytotoxicity on MCF-7 cells more significantly than NIH-3T3 cells. Cell flow cytometry indicated that targeted liposomes uptake was superior to plain (non-targted) liposomes and free drug. Free drug and RB-loaded liposomes interrupted cell cycle in G1. However, amino acid-targeted liposomes arrested cells more than the free drug at this stage. Targeted liposomes reduced cell cycle with more interruption in the G2/M phase compared to the negative control. [ABSTRACT FROM AUTHOR]

Modern drug development increasingly requires comprehensive models that can be utilized in the earliest stages of compound and target discovery. Here we report a phenotypic screening exercise in a high-throughput Organ-on-a-Chip setup. We assessed the inhibitory effect of 1537 protein kinase inhibitors in an angiogenesis assay. Over 4000 micro-vessels were grown under perfusion flow in microfluidic chips, exposed to a cocktail of pro-angiogenic factors and subsequently exposed to the respective kinase inhibitors. Efficacy of compounds was evaluated by reduced angiogenic sprouting, whereas reduced integrity of the main micro-vessel was taken as a measure for toxicity. The screen yielded 53 hits with high anti-angiogenicity and low toxicity, of which 44 were previously unassociated with angiogenic pathways. This study demonstrates that Organ-on-a-Chip models can be screened in high numbers to identify novel compounds and targets. This will ultimately reduce bias in early-stage drug development and increases probability to identify first in class compounds and targets for today's intractable diseases. [ABSTRACT FROM AUTHOR]

Background: Gallbladder cancer (GBC), a highly malignant gastrointestinal tumor, lacks effective therapies. Foxhead box A2 (FOXA2) is a tumor suppressor that is poorly expressed in various human malignancies. This study aimed to ascertain FOXA2 expression in GBC and its relevance to tumor metastasis, and to elucidate its regulatory mechanism with epithelial‐mesenchymal transition (EMT) as an entry point, in the hope of providing a potential therapeutic target for GBC. Methods: FOXA2 expression in GBC tissues was first detected using immunohistochemistry (IHC), followed by correlation analysis with clinicopathological characteristics and survival prognosis. Subsequently, the effects of FOXA2 on GBC cell migration and invasion, as well as EMT induction, were evaluated by scratch, Transwell, RT‐PCR, and Western blot assays, together with animal experimentation. Ultimately, mRNA sequencing was carried out to identify the key downstream target genes of FOXA2 in controlling the EMT process in GBC cells, and dual‐luciferase reporter and chromatin immunoprecipitation assays were used to determine its regulatory mechanism. Results: FOXA2 was underexpressed in GBC tissues and inversely correlated with tumor node metastasis stage, lymph node metastasis, and poor patient prognosis. FOXA2 exerts suppressive effects on EMT and metastasis of GBC in vivo and in vitro. FOXA2 can impede GBC cell migratory and invasive functions and EMT by positively mediating serine protein kinase inhibitor B5 (SERPINB5) expression. Conclusion: FOXA2 directly binds to the SERPINB5 promoter region to stimulate its transcription, thereby modulating the migration and invasion behaviors of GBC cells as well as the EMT process, which might be an effective therapeutic target against GBC. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the pan-cancer landscape of MUTYH alterations and the relationship between MUTYH mutations and potentially actionable biomarkers such as specific genomic alterations, tumor mutational burden, and mutational signatures. We used a large pan-cancer comprehensive genomic dataset from patients profiled (tissue next generation sequencing) during routine clinical care. Overall, 2.8% of 229 120 solid tumors had MUTYH alterations, of which 55% were predicted germline. Thirty tumor types had a 2% or greater MUTYH mutation rate. MUTYH -altered versus -WT cancers had significantly higher tumor mutational burden and more frequent alterations in KRAS G12C , but not in KRAS in general; these observations were statistically significant, especially in colorectal cancers. Across cancers, PD-L1 expression levels (immunohistochemistry) were not associated with MUTYH alteration status. In silico computation demonstrated that MUTYH mutational signatures are associated with higher levels of hydrophobicity (which may reflect higher immunogenicity of neoantigens) relative to several other signature types such as microsatellite instability. Survival of patients with MUTYH -altered versus -WT tumors was similar. In conclusion, comprehensive genomic profiling suggests that several features of MUTYH -altered cancers may be pharmacologically targetable. Drugs such as sotorasib (targeting KRAS G12C) and immune checkpoint inhibitors, targeting the increased mutational load and higher neo-antigen hydrophobicity/immunogenicity merit investigation in MUTYH -mutated malignancies. [ABSTRACT FROM AUTHOR]

Aim. The present study evaluated the therapeutic effects of luteolin in alleviating pulpitis of dental pulp- (DP-) derived microvesicles (MVs) via the inhibition of protein kinase R- (PKR-) mediated inflammation. Methodology. Proteomic analysis of immortalized human dental pulp (DP-1) cell-derived MVs was performed to identify PKR-associated molecules. The effect of luteolin on PKR phosphorylation in DP-1 cells and the expression of tumor necrosis factor-α (TNF-α) in THP-1 macrophage-like cells were validated. The effect of luteolin on cell proliferation was compared with that of chemical PKR inhibitors (C16 and 2-AP) and the unique commercially available sedative guaiacol-parachlorophenol. In the dog experimental pulpitis model, the pulps were treated with (1) saline, (2) guaiacol-parachlorophenol, and (3) luteolin. Sixteen teeth from four dogs were extracted, and the pulp tissues were analyzed using hematoxylin and eosin staining. Immunohistochemical staining was performed to analyze the expression of phosphorylated PKR (pPKR), myeloperoxidase (MPO), and CD68. Experimental endodontic-periodontal complex lesions were established in mouse molar through a silk ligature and simultaneous MV injection. MVs were prepared from DP-1 cells with or without pretreatment with 2-AP or luteolin. A three-dimensional microcomputed tomography analysis was performed on day 7 (n = 6). Periodontal bone resorption volumes were calculated for each group (nonligated–ligated), and the ratio of bone volume to tissue volume was measured. Results. Proteomic analysis identified an endogenous PKR activator, and a protein activator of interferon-induced PKR, also known as PACT, was included in MVs. Luteolin inhibited the expressions of pPKR in DP-1 cells and TNF-α in THP-1 cells with the lowest suppression of cell proliferation. In the dog model of experimental pulpitis, luteolin treatment suppressed the expression of pPKR-, MPO-, and CD68-positive cells in pulp tissues, whereas guaiacol-parachlorophenol treatment caused coagulative necrosis and disruption. In a mouse model of endodontic-periodontal complex lesions, luteolin treatment significantly decreased MV-induced alveolar bone resorption. Conclusion. Luteolin is an effective and safe compound that inhibits PKR activation in DP-derived MVs, enabling pulp preservation. [ABSTRACT FROM AUTHOR]

Accurate modeling of nonbonded interactions between protein kinases and their small molecule inhibitors is essential for structure-based drug design. Quantum chemical methods such as density functional theory (DFT) hold significant promise for quantifying the strengths of these key protein–ligand interactions. However, the accuracy of DFT methods can vary substantially depending on the choice of exchange–correlation functionals and associated basis sets. In this study, a comprehensive benchmarking of nine widely used DFT methods was carried out to identify an optimal approach for quantitative modeling of nonbonded interactions, balancing both accuracy and computational efficiency. From a database of 2139 kinase-inhibitor crystal structures, a diverse library of 49 nonbonded interaction motifs was extracted, encompassing CH–π, π–π stacking, cation–π, hydrogen bonding, and salt bridge interactions. The strengths of nonbonded interaction energies for all 49 motifs were calculated at the advanced CCSD(T)/CBS level of theory, which serve as references for a systematic benchmarking of BLYP, TPSS, B97, ωB97X, B3LYP, M062X, PW6B95, B2PLYP, and PWPB95 functionals with D3BJ dispersion correction alongside def2-SVP, def2-TZVP, and def2-QZVP basis sets. The RI, RIJK, and RIJCOSX approximations were used for selected functionals. It was found that the B3LYP/def2-TZVP and RIJK RI-B2PLYP/def2-QZVP methods delivered the best combination of accuracy and computational efficiency, making them well-suited for efficient modeling of nonbonded interactions responsible for molecular recognition of protein kinase inhibitors in their targets. [ABSTRACT FROM AUTHOR]

Simple Summary: Liposarcoma is the most widespread soft-tissue sarcoma in adults. This review summarizes the molecular genetics and epigenetics of the main liposarcoma subtypes and corresponding aberration in signaling forming the basis for targeted therapy selection. In recent years, specific inhibitors of CDK4/6 and MDM2 and VEGFR/FGFR/PDGFR multi-kinase inhibitors have been proposed for the treatment of liposarcoma. Liposarcoma (LPS) is one of the most common adult soft-tissue sarcomas (STS), characterized by a high diversity of histopathological features as well as to a lesser extent by a spectrum of molecular abnormalities. Current targeted therapies for STS do not include a wide range of drugs and surgical resection is the mainstay of treatment for localized disease in all subtypes, while many LPS patients initially present with or ultimately progress to advanced disease that is either unresectable, metastatic or both. The understanding of the molecular characteristics of liposarcoma subtypes is becoming an important option for the detection of new potential targets and development novel, biology-driven therapies for this disease. Innovative therapies have been introduced and they are currently part of preclinical and clinical studies. In this review, we provide an analysis of the molecular genetics of liposarcoma followed by a discussion of the specific epigenetic changes in these malignancies. Then, we summarize the peculiarities of the key signaling cascades involved in the pathogenesis of the disease and possible novel therapeutic approaches based on a better understanding of subtype-specific disease biology. Although heterogeneity in liposarcoma genetics and phenotype as well as the associated development of resistance to therapy make difficult the introduction of novel therapeutic targets into the clinic, recently a number of targeted therapy drugs were proposed for LPS treatment. The most promising results were shown for CDK4/6 and MDM2 inhibitors as well as for the multi-kinase inhibitors anlotinib and sunitinib. [ABSTRACT FROM AUTHOR]

SUMMARY: Plants are sessile organisms that constantly adapt to their changing environment. The root is exposed to numerous environmental signals ranging from nutrients and water to microbial molecular patterns. These signals can trigger distinct responses including the rapid increase or decrease of root growth. Consequently, using root growth as a readout for signal perception can help decipher which external cues are perceived by roots, and how these signals are integrated. To date, studies measuring root growth responses using large numbers of roots have been limited by a lack of high‐throughput image acquisition, poor scalability of analytical methods, or low spatiotemporal resolution. Here, we developed the Root Walker pipeline, which uses automated microscopes to acquire time‐series images of many roots exposed to controlled treatments with high spatiotemporal resolution, in conjunction with fast and automated image analysis software. We demonstrate the power of Root Walker by quantifying root growth rate responses at different time and throughput scales upon treatment with natural auxin and two mitogen‐associated protein kinase cascade inhibitors. We find a concentration‐dependent root growth response to auxin and reveal the specificity of one MAPK inhibitor. We further demonstrate the ability of Root Walker to conduct genetic screens by performing a genome‐wide association study on 260 accessions in under 2 weeks, revealing known and unknown root growth regulators. Root Walker promises to be a useful toolkit for the plant science community, allowing large‐scale screening of root growth dynamics for a variety of purposes, including genetic screens for root sensing and root growth response mechanisms. Significance Statement: Root Walker: an all‐in‐one pipeline allowing large‐scale screening of root growth dynamics for a variety of purposes. [ABSTRACT FROM AUTHOR]

The efficacy and safety of zanubrutinib, a highly selective next-generation Bruton's tyrosine kinase (BTK) inhibitor, in chronic lymphocytic leukemia and lymphoplasmocytoides immunocytoma seems favorable. Adverse events comprise neutropenia, thrombocytopenia, infection, anemia, and atrial fibrillation. This report describes a 75-year-old man suffering from polydipsia, polyuria, and blurred vision for 10 days. He was diagnosed with lymphoplasmocytoides immunocytoma in 2003. After various therapies, he was started on zanubrutinib in October 2022. A diagnosis of diabetes mellitus had never been established before. On arrival in the emergency department, his plasma glucose was 37.2 mmol/L (671 mg/dL) and glycated hemoglobin (HbA1c) was 14.2%. Circulating antibodies showed positivity for glutamic acid decarboxylase (GAD-65), and his C-peptide level was 1.3 nmol/L (normal range, 0.37-1.47 nmol/L), equivalent to 3.9 ng/mL (normal range 1.1-5.0 ng/mL). From the patient's medical history, it became obvious that the metabolic situation had been problematic for many years, and that diabetes could have been taken into account at least in the summer of 2020 when HbA1c was 6.7%. In patients on tyrosine kinase inhibitors, careful assessment of glycemic control (monitoring HbA1c and blood glucose levels periodically even for nondiabetic patients) is recommended to prevent a major diabetic emergency. [ABSTRACT FROM AUTHOR]

Objective: To provide a comprehensive review of the pharmacokinetics, pharmacodynamics, safety, and efficacy of a new Food and Drug Administration (FDA) approved Bruton's tyrosine kinase inhibitor (BTKi), pirtobrutinib for relapsed/refractory mantle cell lymphoma (r/r MCL). Data sources: A literature search was conducted through PubMed MEDLINE, ClinicalTrials.gov, and the FDA website (January 2018-January 2023) using the following key terms: lymphoma, non-covalent, Bruton's tyrosine kinase (BTK), and relapse. Relevant English language monographs, studies, and abstracts conducted in humans were reviewed and considered. Data summary: Pirtobrutinib, a novel non-covalent BTKi, was granted accelerated approval for treatment of r/r MCL on January 27th, 2023, based on an open-label, multi-center phase 1/2 BRUIN trial. In phase l, 61 patients with r/r MCL received seven dose levels of pirtobrutinib (25–300 mg). There was no reported maximum tolerated dose or dose-limiting toxicities during this study period. In phase 2, 56 r/r MCL evaluable efficacy patients received pirtobrutinib 200 mg daily. The overall response rate (ORR) was 52% (95% CI 38–65). Additionally, patients who received a previous covalent BTKi, ORR was 52% (95% CI 38–66). Neutropenia was the most common adverse reaction reported as a grade 3 or higher. Conclusion: Pirtobrutinib has demonstrated safety and efficacy in heavily pre-treated adult patients with r/r MCL. Advantages of this drug include its usage in patients whose malignancy is resistant to current BTKi, tolerability, and response rate. Multiple clinical trials are underway to determine the efficacy of pirtobrutinib in other B-cell malignancies. [ABSTRACT FROM AUTHOR]

Kirsten rat sarcoma virus (KRAS) is one of the most important and frequently mutated oncogenes in cancer and the mutational prevalence is especially high in many gastrointestinal malignancies, including colorectal cancer and pancreatic ductal adenocarcinoma. The KRAS protein is a small GTPase that functions as an "on/off" switch to activate downstream signaling, mainly through the mitogen-activated protein kinase pathway. KRAS was previously considered undruggable because of biochemical constraints; however, recent breakthroughs have enabled the development of small-molecule inhibitors of KRAS G12C. These drugs were initially approved in lung cancer and have now shown substantial clinical activity in KRAS G12C-mutated pancreatic ductal adenocarcinoma as well as colorectal cancer when combined with anti-EGFR monoclonal antibodies. Early data are encouraging for other gastrointestinal cancers as well and many other combination strategies are being investigated. Several new KRAS G12C inhibitors and novel inhibitors of other KRAS alterations have recently entered the clinic. These molecules employ a variety of innovative mechanisms and have generated intense interest. These novel drugs are especially important as KRAS G12C is rare in gastrointestinal malignancies compared with other KRAS alterations, representing potentially groundbreaking advances. Soon, the rapidly evolving landscape of novel KRAS inhibitors may substantially shift the therapeutic landscape for gastrointestinal cancers and offer meaningful survival improvements. [ABSTRACT FROM AUTHOR]

Ripasudil, a rho-associated protein kinase inhibitor ophthalmic solution, shows a protective effect in preventing excessive scarring in vitro. This study aims to evaluate the safety and efficacy of ripasudil for glaucoma patients submitted to the needling procedure. In this prospective, multicenter, single-arm study, we included 20 eyes of 20 patients with glaucoma who underwent the needling procedure without antimetabolites. All patients administered ripasudil after needling for three months. The primary endpoint of this study was the safety of ripasudil in patients, and the secondary endpoint was the change in IOP at 12 weeks after the needling procedure. No serious complications were found in the patients. One eye experienced pruritus and conjunctival follicle, while another eye had conjunctival follicle. These complications were transient and resolved quickly after discontinuation of ripasudil. The mean preoperative IOP was 14.6 ± 4.6 mmHg, which decreased to 11.0 ± 4.7 mmHg (p = 0.0062) at 1 week postoperatively. The IOP reduction effect continued to 12 weeks (11.8 ± 3.1 mmHg; p = 0.0448). The administration of the ROCK inhibitor, ripasudil, after the needling procedure is safe and effective in maintaining IOP for 12 weeks. [ABSTRACT FROM AUTHOR]

Simple Summary: This study focuses on finding improved treatment strategies for advanced or metastatic synovial sarcoma, which is a rare and aggressive type of soft tissue sarcoma. The researchers tested a combination of two drugs, peposertib and doxorubicin, to see if they could work together to kill synovial sarcoma cells more efficiently. The experiments conducted in cultured cancer cells and mouse models of synovial sarcoma demonstrated that when these drugs were used together, they had a significantly stronger effect against cancer cells compared to using either drug alone. It is noteworthy that the combination could successfully overcome resistance to doxorubicin monotherapy in a patient-derived tumor model. This study also shed light on the underlying molecular mechanisms of this combination effect. Overall, the findings suggest that combining peposertib with doxorubicin could be a promising treatment option for synovial sarcoma patients in the future. Synovial sarcoma is a rare and highly aggressive subtype of soft tissue sarcoma. The clinical challenge posed by advanced or metastatic synovial sarcoma, marked by limited treatment options and suboptimal outcomes, necessitates innovative approaches. The topoisomerase II (Topo II) inhibitor doxorubicin has remained the cornerstone systemic treatment for decades, and there is pressing need for improved therapeutic strategies for these patients. This study highlights the potential to enhance the cytotoxic effects of doxorubicin within well-characterized synovial sarcoma cell lines using the potent and selective DNA-PK inhibitor, peposertib. In vitro investigations unveil a p53-mediated synergistic anti-tumor effect when combining doxorubicin with peposertib. The in vitro findings were substantiated by pronounced anti-tumor effects in mice bearing subcutaneously implanted tumors. A well-tolerated regimen for the combined application was established using both pegylated liposomal doxorubicin (PLD) and unmodified doxorubicin. Notably, the combination of PLD and peposertib displayed enhanced anti-tumor efficacy compared to unmodified doxorubicin at equivalent doses, suggesting an improved therapeutic window—a critical consideration for clinical translation. Efficacy studies in two patient-derived xenograft models of synovial sarcoma, accurately reflecting human metastatic disease, further validate the potential of this combined therapy. These findings align with previous evidence showcasing the synergy between DNA-PK inhibition and Topo II inhibitors in diverse tumor models, including breast and ovarian cancers. Our study extends the potential utility of combined therapy to synovial sarcoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Uveal melanoma (UM) is a rare cancer that forms in the eye. Once the disease becomes metastatic, which occurs in approximately half of the cases, the prognosis is highly dismal with there being no standard treatment, underscoring the dire need to develop novel systemic therapies for UM. In this study, we discovered that two molecular features characteristic of UM, MDM4 overexpression and increased protein kinase C (PKC) activity associated with infrequent p53 mutations and frequent GNAQ/GNA11 mutations, respectively, work together to suppress p53 to confer growth advantage on UM cells. Furthermore, we show that a small-molecule kinase inhibitor CEP-1347 targets MDM4 and PKC at the same time to effectively activate p53 and inhibit the growth of UM cells at clinically feasible concentrations. Thus, CEP-1347 is a unique, dual inhibitor of MDM4 and PKC in UM cells and may become a therapeutic option for refractory UM. Uveal melanoma (UM) is among the most common primary intraocular neoplasms in adults, with limited therapeutic options for advanced/metastatic disease. Since UM is characterized by infrequent p53 mutation coupled with the overexpression of MDM4, a major negative regulator of p53, we aimed to investigate in this study the effects on UM cells of CEP-1347, a novel MDM4 inhibitor with a known safety profile in humans. We also examined the impact of CEP-1347 on the protein kinase C (PKC) pathway, known to play a pivotal role in UM cell growth. High-grade UM cell lines were used to analyze the effects of genetic and pharmacological inhibition of MDM4 and PKC, respectively, as well as those of CEP-1347 treatment, on p53 expression and cell viability. The results showed that, at its clinically relevant concentrations, CEP-1347 reduced not only MDM4 expression but also PKC activity, activated the p53 pathway, and effectively inhibited the growth of UM cells. Importantly, whereas inhibition of either MDM4 expression or PKC activity alone failed to efficiently activate p53 and inhibit cell growth, inhibition of both resulted in effective activation of p53 and inhibition of cell growth. These data suggest that there exists a hitherto unrecognized interaction between MDM4 and PKC to inactivate the p53-dependent growth control in UM cells. CEP-1347, which dually targets MDM4 and PKC, could therefore be a promising therapeutic candidate in the treatment of UM. [ABSTRACT FROM AUTHOR]

Simple Summary: Histone deacetylase (HDAC) inhibitors are anti-cancer agents that have demonstrated efficacy in hematologic malignancies; however, the utility of available agents is limited, owing to narrow therapeutic indices and suboptimal isoform selectivity. Bocodepsin (OKI-179) is a novel, orally bioavailable, Class I-targeting depsipeptide HDAC inhibitor with promising anti-cancer activity in preclinical solid tumor models. In this first-in-human phase I clinical study, we report the safety and tolerability of OKI-179 administered orally daily with intermittent and continuous dosing schedules. OKI-179 was well tolerated with low rates of high-grade adverse events, supporting the potential for the successful combination of OKI-179 with other targeted anti-cancer agents. OKI-179 is currently being investigated in combination with the MEK inhibitor binimetinib in patients with NRAS-mutated melanoma. (1) Background: Histone deacetylases (HDACs) play a critical role in epigenetic signaling in cancer; however, available HDAC inhibitors have limited therapeutic windows and suboptimal pharmacokinetics (PK). This first-in-human phase I dose escalation study evaluated the safety, PK, pharmacodynamics (PDx), and efficacy of the oral Class I-targeting HDAC inhibitor bocodepsin (OKI-179). (2) Patients and Methods: Patients (n = 34) with advanced solid tumors were treated with OKI-179 orally once daily in three schedules: 4 days on 3 days off (4:3), 5 days on 2 days off (5:2), or continuous in 21-day cycles until disease progression or unacceptable toxicity. Single-patient escalation cohorts followed a standard 3 + 3 design. (3) Results: The mean duration of treatment was 81.2 (range 11–447) days. The most frequent adverse events in all patients were nausea (70.6%), fatigue (47.1%), and thrombocytopenia (41.2%). The maximum tolerated dose (MTD) of OKI-179 was 450 mg with 4:3 and 200 mg with continuous dosing. Dose-limiting toxicities included decreased platelet count and nausea. Prolonged disease control was observed, including two patients with platinum-resistant ovarian cancer. Systemic exposure to the active metabolite exceeded the preclinical efficacy threshold at doses lower than the MTD and was temporally associated with increased histone acetylation in circulating T cells. (4) Conclusions: OKI-179 has a manageable safety profile at the recommended phase 2 dose (RP2D) of 300 mg daily on a 4:3 schedule with prophylactic oral antiemetics. OKI-179 is currently being investigated with the MEK inhibitor binimetinib in patients with NRAS-mutated melanoma in the phase 2 Nautilus trial. [ABSTRACT FROM AUTHOR]

Purpose: The ADAURA trial demonstrated the superiority of osimertinib over a placebo with regard to disease-free survival, showing it to be indicated as an adjuvant therapy for treatment of non–small cell lung cancer with mutated epidermal growth factor receptor (EGFR). The aim of the present study was to conduct a cost-utility analysis and an analysis of the budgetary impact of adjuvant therapy with osimertinib in patients with non–small cell lung cancer with mutated EGFR who had undergone resection surgery with curative intent. Methods: Analyses were based on the outcomes of the ADAURA clinical trial and were conducted through a Spanish National Health Service perspective. The outcome measures used were quality-adjusted life years (QALY). Results: The average overall cost of adjuvant treatment with osimertinib over a period of 100 months in the overall sample of trial patients (stages IB-IIIA) was 220,961 €, compared with 197,849 € in the placebo group. Effectiveness, estimated according to QALY, was 6.26 years in the osimertinib group and 5.96 years in the placebo group, with the incremental cost-utility ratio being 77,040 €/QALY. With regard to the budgetary impact, it was estimated that, in 2021, approximately 1130 patients would be subsidiaries to receive osimertinib. This pertains to a difference of 17,375,330 € over 100 months to fund this treatment relative to no treatment. Conclusion: Taking into account a Spanish threshold of 24,000 €/QALY, the reduction in the acquisition cost of osimertinib will have to be greater than 10%, to obtain a cost-effective alternative. [ABSTRACT FROM AUTHOR]

Plant protein phosphatase 2Cs (PP2Cs) function as inhibitors in protein kinase cascades involved in various processes and are crucial participants in both plant development and signaling pathways activated by abiotic stress. In this study, a genome-wide study was conducted on the CqPP2C gene family. A total of putative 117 CqPP2C genes were identified. Comprehensive analyses of physicochemical properties, chromosome localization and subcellular localization were conducted. According to phylogenetic analysis, CqPP2Cs were divided into 13 subfamilies. CqPP2Cs in the same subfamily had similar gene structures, and conserved motifs and all the CqPP2C proteins had the type 2C phosphatase domains. The expansion of CqPP2Cs through gene duplication was primarily driven by segmental duplication, and all duplicated CqPP2Cs underwent evolutionary changes guided by purifying selection. The expression of CqPP2Cs in various tissues under different abiotic stresses was analyzed using RNA-seq data. The findings indicated that CqPP2C genes played a role in regulating both the developmental processes and stress responses of quinoa. Real-time quantitative reverse transcription PCR (qRT-PCR) analysis of six CqPP2C genes in subfamily A revealed that they were up-regulated or down-regulated under salt and drought treatments. Furthermore, the results of yeast two-hybrid assays revealed that subfamily A CqPP2Cs interacted not only with subclass III CqSnRK2s but also with subclass II CqSnRK2s. Subfamily A CqPP2Cs could interact with CqSnRK2s in different combinations and intensities in a variety of biological processes and biological threats. Overall, our results will be useful for understanding the functions of CqPP2C in regulating ABA signals and responding to abiotic stress. [ABSTRACT FROM AUTHOR]

Mitogen‐activated protein kinase 7 (MAPK7) is a serine/threonine protein kinase that belongs to the MAPK family and plays a vital role in various cellular processes such as cell proliferation, differentiation, gene transcription, apoptosis, metabolism, and cell survival. The elevated expression of MAPK7 has been associated with the onset and progression of multiple aggressive tumors in humans, underscoring the potential of targeting MAPK7 pathways in therapeutic research. This pursuit holds promise for the advancement of anticancer drug development by developing potential MAPK7 inhibitors. To look for potential MAPK7 inhibitors, we exploited structure‐based virtual screening of natural products from the ZINC database. First, the Lipinski rule of five criteria was used to filter a large library of ~90,000 natural compounds, followed by ADMET and pan‐assay interference compounds (PAINS) filters. Then, top hits were chosen based on their strong binding affinity as determined by molecular docking. Further, interaction analysis was performed to find effective and specific compounds that can precisely bind to the binding pocket of MAPK7. Consequently, two compounds, ZINC12296700 and ZINC02123081, exhibited significant binding affinity and demonstrated excellent drug‐like properties. All‐atom molecular dynamics simulations for 200 ns confirmed the stability of MAPK7‐ZINC12296700 and MAPK7‐ZINC02123081 docked complexes. According to the molecular mechanics Poisson–Boltzmann surface area investigation, the binding affinities of both complexes were considerable. Overall, the result suggests that ZINC12296700 and ZINC02123081 might be used as promising leads to develop novel MAPK7 inhibitors. Since these compounds would interfere with the kinase activity of MAPK7, therefore, may be implemented to control cell growth and proliferation in cancer after required validations. [ABSTRACT FROM AUTHOR]

The possibility of stratifying patients according to differences in ROS proto‐oncogene 1 (ROS1) fusion partners has been discussed. This study aimed to clarify the clinicopathological differences between two SDC4::ROS1 positive NSCLC cases who had different responses to crizotinib. Cytology and pathology samples from two NSCLC cases with SDC4::ROS1 who were diagnosed and treated with crizotinib at Nihon University Itabashi Hospital were obtained. Case 1 has been well‐controlled with crizotinib for over 5 years, but case 2 was worse and overall survival was 19 months. Sequencing analysis of ROS1 fusion genes was performed by reverse‐transcription‐PCR and Sanger's sequencing methods. In addition, thyroid transcription factor (TTF)‐1, ROS‐1, Ki67, and phosphorylated extracellular signal‐regulated kinase (pERK)1/2 expression were investigated using immunohistochemistry. Sequencing analysis showed SDC4 exon2::ROS1 exon 32 (exon33 deleted) in case 1, and coexistence of SDC4 exon2::ROS1 exon 34 and SDC4 exon2::ROS1 exon35 in case 2. The Ki67 index was not different, but ROS1 and pERK1/2 expression levels tended to be higher in the tumor cells of case 2 than in case 1. Therapeutic response to crizotinib and patients' prognosis in ROS1 rearranged NSCLC may be related to the activation of ROS1 signaling, depending on ROS1 and pERK1/2 overexpression status, even if the ROS1 fusion partner is the same. [ABSTRACT FROM AUTHOR]

Objectives: The primary objective of this study was to investigate the potential synergy between Sorafenib, a multi-kinase inhibitor, and Palbociclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, in the treatment of hormone receptor-positive breast cancer. Specifically, we aimed to determine whether the combination of these two drugs could enhance cell death in breast cancer cell lines. Methods: Cell Culture: Hormone receptor-positive breast cancer cell lines expressing estrogen receptors (ER-positive) and/or progesterone receptors (PR-positive) were selected for the study. Drug Treatment: Cells were treated with Sorafenib, Palbociclib, or a combination of both drugs. Cell Viability Assays: Cell viability and proliferation were assessed using MTT and BrdU assays, respectively. Immunoblotting: Protein expression and phosphorylation levels of key signaling molecules were analyzed to investigate the intracellular pathways affected by drug treatments. Statistical Analysis: Statistical comparisons were made between single-drug and combination-drug treatments to evaluate their effects on cell viability and proliferation. Results: Our study revealed the following key findings: Hormone receptor-positive breast cancer cells were chosen for this study due to their dependence on estrogen and progesterone for growth and division. Sorafenib, a multi-kinase inhibitor, effectively targeted multiple signaling pathways involved in cell proliferation, angiogenesis, and apoptosis, including Raf, VEGFR, PDGFR, and FLT3. Palbociclib, a CDK4/6 inhibitor, arrested cancer cells in the G1 phase of the cell cycle, preventing their progression into the S phase and subsequent proliferation. Contrary to expectations, the combination of Sorafenib and Palbociclib in hormone receptor-positive breast cancer cell lines did not result in enhanced cell death. Instead, it exhibited a proliferative effect. These unexpected results highlight the complexity of intracellular pathways and the potential for cross-talk between signaling pathways when drugs are combined. Conclusion: In conclusion, our study emphasizes the intricate and multifaceted nature of intracellular pathways in hormone receptor-positive breast cancer. The unanticipated proliferative effect of the Sorafenib and Palbociclib combination underscores the importance of considering all possible mechanisms of action when designing drug combinations for cancer treatment. This study serves as a valuable reminder that therapies should not solely depend on the modulation of a single pathway but rather take into account the intricate web of interactions within the cellular environment. Further research is warranted to elucidate the underlying molecular mechanisms responsible for the observed outcomes and to guide the development of more effective treatment strategies for hormone receptor-positive breast cancer. [ABSTRACT FROM AUTHOR]

Background: We investigated the efficacy and health-related quality of life (HRQoL) in patients receiving either ribociclib plus endocrine therapy (ET) or chemotherapy with/without bevacizumab as first-line treatment of metastatic hormone receptor (HR)-positive, HER2-negative breast cancer (BC). Patients and Methods: In this randomized, phase III study (RIBBIT), 38 patients diagnosed with metastatic HR-positive, HER2-negative BC with presence of visceral metastases recruited between May 2018 and December 2020 were randomly assigned in a 1:1 ratio to either arm A (ribociclib + ET) or arm B (chemotherapy with/without bevacizumab) at 12 sites in Germany. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), overall survival (OS), patient-reported HRQoL, and frequency and type of adverse events. During study conduction, the recruitment rate was persistently and considerably lower than originally expected. Therefore, the recruitment was ended prematurely. The study was initially designed to enroll and randomize 158 patients. Results: Median [95% CI] PFS was 27.3 months [19.1 – NA, parameter not estimable] in arm A and 15.8 months [8.2 – NA] in arm B. Complete responses were achieved only in arm A (n = 2, 10.5%). The ORR [95% CI] between arm A (57.9% [33.5–79.7]) and arm B (52.6% [28.9–75.6]) was comparable. Median OS [95% CI] was not reached in arm A, while in arm B median OS was 28.4 months [25.0 – NA]. Patients in arm A reported less burden by side-effects. No new safety signals emerged. Conclusion: Treatment of patients with visceral metastatic HR-positive, HER2-negative BC with ribociclib in combination with ET showed a tendency toward a more favorable clinical outcome. Despite small numbers of patients and sites, this head-to-head comparison with chemotherapy supports the use of ribociclib with ET in patients with visceral metastasis at risk of fast disease progression. [ABSTRACT FROM AUTHOR]

Background Cancers with non-V600 BRAF-activating alterations have no matched therapy. Preclinical data suggest that these tumors depend on ERK signaling; however, clinical response to MEK/ERK inhibitors has overall been low. We hypothesized that a narrow therapeutic index, driven by ERK inhibition in healthy (wild-type) tissues, limits the efficacy of these inhibitors. As these mutants signal as activated dimers, we further hypothesized that RAF inhibitors given concurrently would improve the therapeutic index by opposing ERK inhibition in normal tissues and not activate ERK in the already activated tumor. Materials and Methods Using cell lines and patient-derived xenografts, we evaluated the effect of RAF inhibition, alone and in combination with MEK/ERK inhibitors. We then undertook a phase I/II clinical trial of a higher dose of the MEK inhibitor binimetinib combined with the RAF inhibitor encorafenib in patients with advanced cancer with activating non-V600 BRAF alterations. Results RAF inhibition led to modest inhibition of signaling and growth in activated non-V600 BRAF preclinical models and allowed higher dose of MEK/ERK inhibitors in vivo for more profound tumor regression. Fifteen patients received binimetinib 60 mg twice daily plus encorafenib 450 mg daily (6 gastrointestinal primaries, 6 genitourinary primaries, 3 melanoma, and 2 lung cancer; 7 BRAF mutations and 8 BRAF fusions). Treatment was well tolerated without dose-limiting toxicities. One patient had a confirmed partial response, 8 had stable disease, and 6 had radiographic or clinical progression as best response. On-treatment biopsies revealed incomplete ERK pathway inhibition. Conclusion Combined RAF and MEK inhibition does not sufficiently inhibit activated non-V600 BRAF-mutant tumors in patients. [ABSTRACT FROM AUTHOR]

Background This study aimed to evaluate the safety, pharmacokinetics (PKs), and preliminary activity of LY3405105, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), in patients with advanced solid tumors. Materials and Methods LY3405105 monotherapy was given once daily (QD; part A1) or thrice weekly (TIW; part A2) starting at 1 and 2 mg orally, respectively, and escalated per a Bayesian design in adult patients. The primary endpoint was safety, and secondary endpoints included PKs and antitumor activity. Results Fifty-four patients were enrolled: 43 in part A1 and 11 in part A2. Seven patients had dose-limiting toxicities, all in part A1 (45 mg: n  = 3; 35 mg: n  = 3; 25 mg: n  = 1). Thirty-five patients (64.8%) reported at least one treatment-related adverse event (TRAE). TRAEs (≥10%) were diarrhea, nausea, fatigue, vomiting, abdominal pain, anemia, asthenia, and decreased platelet count. QD dosing showed sustained exposure with less peak-trough fluctuation compared to TIW dosing. Median time to maximum concentration was 1-2 hours and half-life was 15-19 hours. CDK7-target occupancy in skin and peripheral blood on day 15 was dose-dependent and reached near maximal occupancy of 75% at ≥15 mg QD. The maximum tolerated dose (MTD) was 20 mg QD. Twelve patients in part A1 (27.9%) and 5 patients in part A2 (45.5%) had a best overall response of stable disease. No complete response or partial response was observed. Conclusion The MTD of LY3405105 monotherapy was 20 mg QD. The most common toxicities were gastrointestinal adverse events, myelosuppression, fatigue, and asthenia. Limited clinical activity was observed in this phase I trial, and there are no plans for further development. ClinicalTrials.gov Identifier NCT03770494. [ABSTRACT FROM AUTHOR]

Background: Melanoma cancer represents the most lethal type of skin cancer originating from the malignant transformation of melanocyte cells. Almost 50% of melanomas show the activation of BRAF mutations. The identification and characterization of BRAF mutations led to the development of specific drugs that radically changed the therapeutic approach to melanoma. Methods: We conducted a narrative review of the literature according to a written protocol before conducting the study. This article is based on previously conducted studies. We identified articles by searching electronic databases (Medline, Google Scholar and PubMed). We used a combination of "melanoma", "Braf-Mek inhibitors", " targeted therapy" and "oral side effects". Results: Eighteen studies were reported in this article showing the relationship between the use of targeted therapy in melanoma cancer and the development of oral side effects, such as mucositis, hyperkeratosis and cellular proliferation. Conclusion: Targeted therapy plays an important role in the treatment of melanoma cancer, showing a notable increase in response rate, prolonged progression-free survival and overall survival in BRAF-mutated melanoma patients. Oral side effects represent a common finding over the course of treatment. However, these adverse effects can be easily managed in a multidisciplinary approach involving collaboration between medical oncologists and dental doctors. [ABSTRACT FROM AUTHOR]

Simple Summary: Neurofibromatosis 1 (NF1) is a genetic disorder that predisposes patients to developing nerve sheath tumors that are difficult to treat. There is currently just one drug approved for the treatment of NF1-related inoperable plexiform neurofibromas (for a limited patient population), highlighting the need for further drug discovery in this field. High-throughput screening data are used to guide drug development, but identifying and selecting promising targets can be complex. The aim of our study is to improve the value of high-throughput screening data by combining potency and effectiveness into single-value indices (S, ΔS, and ΔS mean), which are used to assess and rank drug sensitivity and drug resistance in cells exposed to potential therapeutic drugs. Our approach with S indices was applied to cell lines derived from plexiform neurofibromas of patients with NF1 gene mutations. The use of S indices provides valuable additional and independent information for discriminating among candidate compounds for follow-up pre-clinical evaluations. Background: Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by heterozygous germline NF1 gene mutations that predispose patients to developing plexiform neurofibromas, which are benign but often disfiguring tumors of the peripheral nerve sheath induced by loss of heterozygosity at the NF1 locus. These can progress to malignant peripheral nerve sheath tumors (MPNSTs). There are no approved drug treatments for adults with NF1-related inoperable plexiform neurofibromas, and only one drug (selumetinib), which is an FDA-approved targeted therapy for the treatment of symptomatic pediatric plexiform neurofibromas, highlighting the need for additional drug screening and development. In high-throughput screening, the effectiveness of drugs against cell lines is often assessed by measuring in vitro potency (AC50) or the area under the curve (AUC). However, the variability of dose–response curves across drugs and cell lines and the frequency of partial effectiveness suggest that these measures alone fail to provide a full picture of overall efficacy. Methods: Using concentration–response data, we combined response effectiveness (EFF) and potency (AC50) into (a) a score characterizing the effect of a compound on a single cell line, S = log[EFF/AC50], and (b) a relative score, ΔS, characterizing the relative difference between a reference (e.g., non-tumor) and test (tumor) cell line. ΔS was applied to data from high-throughput screening (HTS) of a drug panel tested on NF1−/− tumor cells, using immortalized non-tumor NF1+/− cells as a reference. Results: We identified drugs with sensitivity, targeting expected pathways, such as MAPK-ERK and PI3K-AKT, as well as serotonin-related targets, among others. The ΔS technique used here, in tandem with a supplemental ΔS web tool, simplifies HTS analysis and may provide a springboard for further investigations into drug response in NF1-related cancers. The tool may also prove useful for drug development in a variety of other cancers. [ABSTRACT FROM AUTHOR]

Protein kinases are one of the most significant drug targets in the human proteome, historically harnessed for the treatment of cancer, cardiovascular disease, and a growing number of other conditions, including autoimmune and inflammatory processes. Since the approval of the first kinase inhibitors in the late 1990s and early 2000s, the field has grown exponentially, comprising 98 approved therapeutics to date, 37 of which were approved between 2016 and 2021. While many of these small-molecule protein kinase inhibitors that interact orthosterically with the protein kinase ATP binding pocket have been massively successful for oncological indications, their poor selectively for protein kinase isozymes have limited them due to toxicities in their application to other disease spaces. Thus, recent attention has turned to the use of alternative allosteric binding mechanisms and improved drug platforms such as modified peptides to design protein kinase modulators with enhanced selectivity and other pharmacological properties. Herein we review the role of different protein kinase C (PKC) isoforms in cancer and cardiovascular disease, with particular attention to PKC-family inhibitors. We discuss translational examples and carefully consider the advantages and limitations of each compound (Part I). We also discuss the recent advances in the field of protein kinase modulators, leverage molecular docking to model inhibitor–kinase interactions, and propose mechanisms of action that will aid in the design of next-generation protein kinase modulators (Part II). [ABSTRACT FROM AUTHOR]

Human Wharton's jelly mesenchymal stem cells (hWJ-MSCs) are of great interest in tissue engineering. We obtained hWJ-MSCs from four patients, and then we stimulated their chondrogenic phenotype formation in vitro by adding resveratrol (during cell expansion) and a canonical Wnt pathway activator, LiCl, as well as a Rho-associated protein kinase inhibitor, Y27632 (during differentiation). The effects of the added reagents on the formation of hWJ-MSC sheets destined to repair osteochondral injuries were investigated. Three-dimensional hWJ-MSC sheets grown on P(NIPAM-co-NtBA)-based matrices were characterized in vitro and in vivo. The combination of resveratrol and LiCl showed effects on hWJ-MSC sheets similar to those of the basal chondrogenic medium. Adding Y27632 decreased both the proportion of hypertrophied cells and the expression of the hyaline cartilage markers. In vitro, DMSO was observed to impede the effects of the chondrogenic factors. The mouse knee defect model experiment revealed that hWJ-MSC sheets grown with the addition of resveratrol and Y27632 were well integrated with the surrounding tissues; however, after 3 months, the restored tissue was identical to that of the naturally healed cartilage injury. Thus, the combination of chondrogenic supplements may not always have additive effects on the progress of cell culture and could be neutralized by the microenvironment after transplantation. [ABSTRACT FROM AUTHOR]

SGK1 is a serine/threonine kinase involved in several neurodegenerative-related pathways such as apoptosis, neuroinflammation, ionic channel regulation, and autophagy, among others. Despite its potential role as a pharmacological target against this kind of diseases, there are no reported inhibitors able to cross the BBB so far, being a field yet to be explored. In this context, a structure-based virtual screening against this kinase was performed, pointing out the deazapurine moiety as an interesting and easy-to-derivatize scaffold. Moreover, these inhibitors are able to i) exert neuroprotection in an in vitro model of AD and ii) block mitophagy in a PRKN-independent manner, reinforcing the hypothesis of SGK1 inhibitors as neuroprotective chemical tools. [ABSTRACT FROM AUTHOR]

Protein phosphorylation plays an important role in cellular pathways, including cell cycle regulation, metabolism, differentiation and survival. The protein kinase superfamily network consists of 518 members involved in intrinsic or extrinsic interaction processes. Protein kinases are divided into two categories based on their ability to phosphorylate tyrosine, serine, and threonine residues. The complexity of the system implies its vulnerability. Any changes in the pathways of protein kinases may be implicated in pathological processes. Therefore, they are regarded as having an important role in human diseases and represent prospective therapeutic targets. This article provides a review of the protein kinase inhibitors approved by the FDA. Finally, we summarize the mechanism of action of protein kinases, including their role in the development and progression of protein kinase-related roles in various pathological conditions and the future therapeutic potential of protein kinase inhibitors, along with links to protein kinase databases. Further clinical studies aimed at examining the sequence of protein kinase inhibitor availability would better utilize current protein kinase inhibitors in diseases. Additionally, this review may help researchers and biochemists find new potent and selective protein kinase inhibitors and provide more indications for using existing drugs. [ABSTRACT FROM AUTHOR]

Introduction: Cases of osteonecrosis of the jaw have been reported by dental surgeons to the pharmacovigilance center in Rennes, France, occurring among patients treated with palbociclib, a cyclin-dependent kinase 4/6 inhibitor. Although this event was not expected with the drug, a safety signal was raised. Describing a local case series, the aim of our study was to identify specific patterns that might suggest a triggering role for these drugs, and to discuss pathophysiological hypotheses. Materials and methods: A retrospective case series of patients exposed to cyclin-dependent kinase 4/6 inhibitors between 2016 and 2020 with a diagnosis of osteonecrosis of the jaw at the Rennes Dental Care Center was analyzed. The descriptive analysis was conducted on patient demographics, breast cancer characteristics, osteonecrosis of the jaw, biological data, and exposure to cyclin-dependent kinase 4/6 inhibitors. Results: We identified eight cases, most of them at stages 0–1 (62.5%). Four patients were still exposed to palbociclib at the time of diagnosis and four had discontinued the treatment before the diagnosis. Chronological imputability could not be excluded given the drug's half-life and the variable intervals of dental monitoring from one patient to another. All patients had at least one dental osteonecrosis risk factor (including dental extraction, dentures, and denosumab exposure at the time of diagnosis). Neutropenia and mucositis were not systematically reported at the time of diagnosis. The anatomopathological characteristics were nonspecific. Conclusion: We did not identify a specific pattern that could suggest a triggering role of palbociclib in the development of ONJ. [ABSTRACT FROM AUTHOR]

Succinic acid diamides containing two pharmacophoric fragments, one of which is 2amino-pyrimidine, and the other, N-methylpiperazine, 2-aminopyrimidine, or substituted aniline moiety, were synthesized in two steps. The synthetic scheme included acylation of substituted (pyrimidin-2-ylamino)aniline or pyrimidin-2-amine with succinic anhydride and the subsequent acylation of another heterocyclic or aromatic amine with the resulting pyrimidine-substituted succinic acid monoamide. The key intermediate products in the synthesis are succinic acid anilides. The acylation heterocyclic or aromatic amines with substituted succinic acid monochloride or amidation of succinic acid benzotriazolyl ester gave the corresponding succinic acid diamides as potential inhibitors of enzymes mediating tumorigenic processes. [ABSTRACT FROM AUTHOR]

Simple Summary: This study explores the therapeutic effect of the combination of BRAF and MEK inhibitors (BRAFi + MEKi) on NRAS-mutated melanomas in vitro, in preclinical in vivo models using patient-derived xenografts (PDXs) and in an individual healing attempt of one patient. NRAS mutations are known to drive aggressive tumor growth and pose challenges for current treatments. This study aimed to assess the efficacy and safety of BRAFi + MEKi combination therapy in NRAS-mutant melanomas. This research seeks to provide critical insights into potential precision therapies for NRAS-mutant melanoma patients, ultimately advancing melanoma therapeutics and improving patient outcomes. Introduction: Patients with NRAS-mutant metastatic melanoma often have an aggressive disease requiring a fast-acting, effective therapy. The MEK inhibitor binimetinib shows an overall response rate of 15% in patients with NRAS-mutant melanoma, providing a backbone for combination strategies. Our previous studies demonstrated that in NRAS-mutant melanoma, the antitumor activity of the MEK inhibitor binimetinib was significantly potentiated by the BRAFV600E/K inhibitor encorafenib through the induction of ER stress, leading to melanoma cell death by apoptotic mechanisms. Encorafenib combined with binimetinib was well tolerated in a phase III trial showing potent antitumor activity in BRAF-mutant melanoma, making a rapid evaluation in NRAS-mutant melanoma imminently feasible. These data provide a mechanistic rationale for the evaluation of binimetinib combined with encorafenib in preclinical and clinical studies on NRAS-mutant metastatic melanoma. Methods: The combination of BRAFi plus MEKi was tested in a monolayer culture of patient-derived cell lines and in corresponding patient-derived tissue slice cultures of NRAS-mutant melanoma. To investigate the treatment in vivo, NSG (NOD. Cg-Prkdcscid Il2rgtm1Wjl/SzJ) mice were subcutaneously injected with three different BRAF wild-type melanoma models harboring oncogenic NRAS mutations and treated orally with encorafenib (6 mg/kg body weight, daily) with or without binimetinib (8 mg/kg body weight, twice daily). In parallel, an individual healing attempt was carried out by treating one patient with an NRAS-mutated tumor. Results: Encorafenib was able to enhance the inhibitory effect on cell growth of binimetinib only in the cell line SKMel147 in vitro. It failed to enhance the apoptotic effect found in two other NRAS-mutated cell lines. Encorafenib led to a hyperactivation of ERK which could be reduced with the combinational treatment. In two of the three patient-derived tissue slice culture models of NRAS-mutant melanomas, a slight tendency of a combinatorial effect was seen which was not significant. Encorafenib showed a slight induction of the ER stress genes ATF4, CHOP, and NUPR1. The combinational treatment was able to enhance this effect, but not significantly. In the mouse model, the combination therapy of encorafenib with binimetinib resulted in reduced tumor growth compared to the control and encorafenib groups; however, the best effect in terms of tumor growth inhibition was measured in the binimetinib therapy group. The therapy showed no effect in an individual healing attempt for a patient suffering from metastatic, therapy-refractory NRAS-mutated melanoma. Conclusion: In in vitro and ex vivo settings, the combination therapy was observed to elicit a response; however, it did not amplify the efficacy observed with binimetinib alone, whereas in a patient, the combinational treatment remained ineffective. The preclinical in vivo data showed no increased combinatorial effect. However, the in vivo effect of binimetinib as monotherapy was unexpectedly high in the tested regimen. Nevertheless, binimetinib proved to be advantageous in the treatment of melanoma in vivo and led to high rates of apoptosis in vitro; hence, it still seems to be a good base for combination with other substances in the treatment of patients with NRAS-mutant melanoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Recent research has revealed a possible synergy between kinase inhibitors and immunotherapy in the treatment of breast cancer. Kinase inhibitors can modulate the tumor microenvironment, making it more receptive to the infiltration and activation of immune cells. This modulation increases the efficacy of subsequent immunotherapeutic interventions, such as immune checkpoint inhibitors. Moreover, targeting specific kinase pathways may reverse the immune evasion mechanisms employed by tumor cells, making them more susceptible to immune recognition and destruction. This dual approach promises to improve response rates and outcomes in breast cancer patients, particularly in kinase-disrupted subtypes. The convergence of kinase inhibitors and immunotherapy represents an exciting frontier in breast cancer treatment. Thus, in this review, we will examine these combinations and their potential impact on the efficacy of responses to these treatments. Cancer is one of the world's most significant health problems today. Currently, breast cancer has globally surpassed lung cancer as the most commonly diagnosed cancer in women. In 2020, an estimated 2,261,419 new cases were diagnosed in women worldwide. Therefore, there is a need to understand the processes that can help us better treat this disease. In recent years, research in the fight against cancer has often been based on two treatment modalities. One of them is the use of protein kinase inhibitors, which have been instrumental in the development of new therapeutic strategies. Another crucial route is the use of immunotherapy, which has been touted as a great promise for cancer treatment. Protein kinase alterations can interfere with the effectiveness of other treatments, such as immunotherapy. In this review, we will analyze the role played by protein kinase alterations in breast cancer and their possible impact on the effectiveness of the response to immunotherapy treatments. [ABSTRACT FROM AUTHOR]

Peposertib is an orally administered inhibitor of DNA‐dependent protein kinase. We evaluated the effect of food on its pharmacokinetics, and examined the pharmacokinetics of an oral suspension (OS) of disintegrated tablets, in a phase I, open‐label, crossover three‐period study (NCT04702698). Twelve healthy volunteers were randomized to one of six treatment sequences. They received a single dose of peposertib 100 mg as film‐coated tablets under fasted or fed conditions ("tablet fasted" or "tablet fed") or as an OS under fasted conditions ("OS fasted"), with washout between treatments. Using healthy volunteers was possible because, despite its mechanism of action being suppression of DNA repair, peposertib has shown no genotoxic effect in animals. A mild food effect was observed with peposertib tablets. Fed‐to‐fasted ratios were: area under the curve from time 0 to time t (AUC0–t), 123.81% (90% confidence interval [CI]: 108.04, 141.87%); AUC from zero to infinity (AUC0–∞), 110.28% (90% CI 100.71, 120.77%); and maximum concentration (Cmax) 104.47% (90% CI: 79.15, 137.90%). Cmax was delayed under fed conditions (median time to maximum concentration [Tmax] was 3.5 h [tablet fed] vs. 1 h [tablet fasted]). OS‐to‐tablet (fasted) ratios were: AUC0–t, 124.83% (90% CI: 111.50%, 139.76%); AUC0–∞, 119.05% (90% CI: 104.47, 135.67%); and Cmax 173.29% (90% CI: 135.78, 221.16%). Median Tmax was 0.5 h (OS fasted) versus 1 h (tablet). All treatments were well‐tolerated in healthy volunteers. Peposertib tablets can be taken with or without food; if combined with chemotherapy or radiotherapy, the delay in Cmax must be considered to optimize the chemo‐ or radiosensitizing effect. The peposertib OS form represents an alternative route of administration in patients with specific cancers causing dysphagia. However, the OS form should be part of future dose optimization strategies in relevant settings. [ABSTRACT FROM AUTHOR]

The field of immune based therapeutics for treatment of common chronic illnesses has exploded leading to significant improvement in the disease processes but a downstream impact on infections. Janus kinase (JAK) inhibitors and Bruton Tyrosine kinase (BTK) inhibitors are becoming more widely used in treatment of chronic inflammatory diseases and chronic leukemias because of simplicity of oral administration. As such, many patients will have improvement in their underlying illnesses and will have greater flexibility to travel. Thus, it is important for travel medicine practitioners to be aware of these agents, their adverse effects and impact on drug interactions and immunizations. [ABSTRACT FROM AUTHOR]

Shared decision-making involves patients engaging with their physicians to make informed decisions regarding treatment selection, a process that empowers patients and ensures that treatment decisions reflect their individual values and preferences. However, shared decision-making can be challenging to implement for various reasons, including time, staffing, or resource limitations at community practices and differences in patients' cultural backgrounds or health literacy. In this podcast, we discuss how to ensure that individual patients' needs and concerns are addressed, including an overview of different approaches for initial consultations, strategies for tailoring conversations based on a patient's background or health literacy, and trustworthy resources that can help improve patients' understanding. As an illustrative example, we focus on how to implement shared decision-making to address the needs of a patient with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer who is eligible for combination therapy with a cyclin-dependent kinase 4/6 inhibitor plus an aromatase inhibitor. Overall, this podcast illustrates how shared decision-making is an achievable goal, even in small or underresourced practices, and provides an instructive guide on how to facilitate shared decision-making for patients with HR+/HER2− metastatic breast cancer. BckE49qAyYLe9j8jEQBXts Podcast Discussion (MP4 29880 KB) Infographic: [ABSTRACT FROM AUTHOR]

Clear cell renal cell carcinoma (CC-RCC) remains one of the most deadly forms of kidney cancer despite recent advancements in targeted therapeutics, including tyrosine kinase and immune checkpoint inhibitors. Unfortunately, these therapies have not been able to show better than a 16% complete response rate. In this study we evaluated a cyclin-dependent kinase inhibitor, Dinaciclib, as a potential new targeted therapeutic for CC-RCC. In vitro, Dinaciclib showed anti-proliferative and pro-apoptotic effects on CC-RCC cell lines in Cell Titer Glo, Crystal Violet, FACS-based cell cycle analysis, and TUNEL assays. Additionally, these responses were accompanied by a reduction in phospho-Rb and pro-survival MCL-1 cell signaling responses, as well as the induction of caspase 3 and PARP cleavage. In vivo, Dinaciclib efficiently inhibited primary tumor growth in an orthotopic, patient-derived xenograft-based CC-RCC mouse model. Importantly, Dinaciclib targeted both CD105+ cancer stem cells (CSCs) and CD105- non-CSCs in vivo. Moreover, normal cell lines, as well as a CC-RCC cell line with re-expressed von-Hippel Lindau (VHL) tumor suppressor gene, were protected from Dinaciclib-induced cytotoxicity when not actively dividing, indicating an effective therapeutic window due to synthetic lethality of Dinaciclib treatment with VHL loss. Thus, Dinaciclib represents a novel potential therapeutic for CC-RCC.

Small-molecule FLT3 inhibitors have recently improved clinical outcomes for patients with FLT3-mutant acute myeloid leukemia (AML) after many years of development, but resistance remains an important clinical problem. FF-10101 is the first irreversible, covalent inhibitor of FLT3 which has previously shown activity against FLT3 tyrosine kinase inhibitor resistance-causing FLT3 F691L and D835 mutations. We report that FF-10101 is also active against an expanded panel of clinically identified FLT3 mutations associated with resistance to other FLT3 inhibitors. We also demonstrate that FF-10101 can potentially address resistance mechanisms associated with growth factors present in the bone marrow microenvironment but is vulnerable to mutation at C695, the amino acid required for covalent FLT3 binding. These data suggest that FF-10101 possesses a favorable resistance profile that may contribute to improved single-agent efficacy when used in patients with FLT3-mutant AML.