cyclin-d1 and abemaciclib

Uncontrolled cellular proliferation, mediated by dysregulation of the cell-cycle machinery and activation of cyclin-dependent kinases (CDKs) to promote cell-cycle progression, lies at the heart of cancer as a pathological process. Clinical implementation of first-generation, nonselective CDK inhibitors, designed to inhibit this proliferation, was originally hampered by the high risk of toxicity and lack of efficacy noted with these agents. The emergence of a new generation of selective CDK4/6 inhibitors, including ribociclib, abemaciclib and palbociclib, has enabled tumour types in which CDK4/6 has a pivotal role in the G1-to-S-phase cell-cycle transition to be targeted with improved effectiveness, and fewer adverse effects. Results of pivotal phase III trials investigating palbociclib in patients with advanced-stage oestrogen receptor (ER)-positive breast cancer have demonstrated a substantial improvement in progression-free survival, with a well-tolerated toxicity profile. Mechanisms of acquired resistance to CDK4/6 inhibitors are beginning to emerge that, although unwelcome, might enable rational post-CDK4/6 inhibitor therapeutic strategies to be identified. Extending the use of CDK4/6 inhibitors beyond ER-positive breast cancer is challenging, and will likely require biomarkers that are predictive of a response, and the use of combination therapies in order to optimize CDK4/6 targeting.

Topics: Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Breast Neoplasms; Cell Cycle; Clinical Trials as Topic; Cyclin D1; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Forecasting; Humans; Molecular Targeted Therapy; Neoplasms; Piperazines; Purines; Pyridines

Topics: Aminopyridines; Animals; Benzimidazoles; Carcinoma, Small Cell; Cell Line, Tumor; Cell Survival; Chromatin Immunoprecipitation; Cyclin D1; DNA Helicases; Female; Humans; Hypercalcemia; Mice; Mice, SCID; Nuclear Proteins; Ovarian Neoplasms; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines; RNA, Small Interfering; Transcription Factors

Ewing sarcoma (ES) is a rare and highly malignant cancer that occurs in the bone and surrounding tissue of children and adolescents. The. Using Western blot, high-content imaging, flow cytometry, ELISA, RNA sequencing, and CpG methylation assays, we characterized the. Abemaciclib induced quiescence in ES cell lines via a G. Collectively, our data demonstrate that the antitumor effects of abemaciclib in preclinical ES models are multifaceted and include cell-cycle inhibition, DNA demethylation, and immunogenic changes.

Topics: Aminopyridines; Animals; Benzimidazoles; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Disease Models, Animal; DNA (Cytosine-5-)-Methyltransferase 1; DNA Methylation; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Humans; Interferons; Mice; Sarcoma, Ewing; Signal Transduction; Xenograft Model Antitumor Assays

The genes encoding MDM2 and CDK4 are frequently co-amplified in sarcomas, and inhibitors to both targets are approved or clinically tested for therapy. However, we show that inhibitors of MDM2 and CDK4 antagonize each other in their cytotoxicity towards sarcoma cells. CDK4 inhibition attenuates the induction of p53-responsive genes upon MDM2 inhibition. Moreover, the p53 response was also attenuated when co-depleting MDM2 and CDK4 with siRNA, compared to MDM2 single knockdown. The complexes of p53 and MDM2, as well as CDK4 and Cyclin D1, physically associated with each other, suggesting direct regulation of p53 by CDK4. Interestingly, CDK4 inhibition did not reduce p53 binding or histone acetylation at promoters, but rather attenuated the subsequent recruitment of RNA Polymerase II. Taken together, our results suggest that caution must be used when considering combined CDK4 and MDM2 inhibition for patient treatment. Moreover, they uncover a hitherto unknown role for CDK4 and Cyclin D1 in sustaining p53 activity.

Topics: Aminopyridines; Antineoplastic Agents; Benzimidazoles; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Cyclin-Dependent Kinase 4; Humans; Piperazines; Proto-Oncogene Proteins c-mdm2; Purines; Pyridines; RNA Interference; RNA, Small Interfering; Sarcoma; Tumor Suppressor Protein p53

Overall survival remains very poor for patients diagnosed as having head and neck squamous cell carcinoma (HNSCC). Identification of additional biomarkers and novel therapeutic strategies are important for improving patient outcomes. Patient-derived xenografts (PDXs), generated by implanting fresh tumor tissue directly from patients into immunodeficient mice, recapitulate many of the features of their corresponding clinical cancers, including histopathological and molecular profiles. Using a large collection of PDX models of HNSCC, we demonstrate that rapid engraftment into immunocompromised mice is highly prognostic and show that genomic deregulation of the G1/S checkpoint pathway correlates with engraftment. Furthermore, CCND1 and CDKN2A genomic alterations are predictive of response to the CDK4and CDK6 inhibitor abemaciclib. Overall, our study supports the pursuit of CDK4 and CDK6 inhibitors as a therapeutic strategy for a substantial proportion of HNSCC patients and demonstrates the potential of using PDX models to identify targeted therapies that will benefit patients who have the poorest outcomes.

Topics: Aminopyridines; Animals; Base Sequence; Benzimidazoles; Cyclin D1; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Cyclin-Dependent Kinase Inhibitor p16; Female; Humans; Male; Mice, Inbred NOD; Mice, SCID; Middle Aged; Multivariate Analysis; Mutation; Neoplasm Recurrence, Local; Precision Medicine; Prognosis; Regression Analysis; Risk Factors; Squamous Cell Carcinoma of Head and Neck; Survival Analysis; Treatment Outcome; Xenograft Model Antitumor Assays

B-RAF selective inhibitors, including vemurafenib, were recently developed as effective therapies for melanoma patients with B-RAF V600E mutation. However, most patients treated with vemurafenib eventually develop resistance largely due to reactivation of MAPK signaling. Inhibitors of MAPK signaling, including MEK1/2 inhibitor trametinib, failed to show significant clinical benefit in patients with acquired resistance to vemurafenib. Here, we describe that cell lines with acquired resistance to vemurafenib show reactivation of MAPK signaling and upregulation of cyclin D1 and are sensitive to inhibition of LY2835219, a selective inhibitor of cyclin-dependent kinase (CDK) 4/6. LY2835219 was demonstrated to inhibit growth of melanoma A375 tumor xenografts and delay tumor recurrence in combination with vemurafenib. Furthermore, we developed an in vivo vemurafenib-resistant model by continuous administration of vemurafenib in A375 xenografts. Consistently, we found that MAPK is reactivated and cyclin D1 is elevated in vemurafenib-resistant tumors, as well as in the resistant cell lines derived from these tumors. Importantly, LY2835219 exhibited tumor growth regression in a vemurafenib-resistant model. Mechanistic analysis revealed that LY2835219 induced apoptotic cell death in a concentration-dependent manner in vemurafenib-resistant cells whereas it primarily mediated cell-cycle G1 arrest in the parental cells. Similarly, RNAi-mediated knockdown of cyclin D1 induced significantly higher rate of apoptosis in the resistant cells than in parental cells, suggesting that elevated cyclin D1 activity is important for the survival of vemurafenib-resistant cells. Altogether, we propose that targeting cyclin D1-CDK4/6 signaling by LY2835219 is an effective strategy to overcome MAPK-mediated resistance to B-RAF inhibitors in B-RAF V600E melanoma.

Topics: Aminopyridines; Animals; Apoptosis; Benzimidazoles; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Drug Resistance, Neoplasm; Female; Humans; Indoles; MAP Kinase Signaling System; Mice; Mice, Nude; Protein Kinase Inhibitors; Signal Transduction; Sulfonamides; Transfection; Up-Regulation; Vemurafenib; Xenograft Model Antitumor Assays