Journal Article

Efficacy of CDK4/6 inhibitors in preclinical models of malignant pleural mesothelioma

Gausachs, Mireia, Nadal, Ernest, Alay, Ania, Pros, Eva, Vidal, August, Dawson, Alan, Ruffinelli, José C., Dorca, Eduard, Cordero, David, Llatjós, Roger, Saigí, Maria, Padrones, Susana, Martínez-Iniesta, Maria, Ramos, Ricard, Solé, Xavi, Aso, Samantha, Hernández-Madrigal, Miguel, Escobar, Ignacio, Sánchez-Céspedes, Montse, Varela, Mar, Aliagas, Elisabet, Palmero, Ramón, Muñoz-Pinedo, Cristina, Sharkley, Annabel J., Villanueva, Alberto, Fennell, Dean, Busacca, Sara

2021

Overview

Background There is no effective therapy for patients with malignant pleural mesothelioma (MPM) who progressed to platinum-based chemotherapy and immunotherapy. Methods We aimed to investigate the antitumor activity of CDK4/6 inhibitors using in vitro and in vivo preclinical models of MPM. Results Based on publicly available transcriptomic data of MPM, patients with CDK4 or CDK6 overexpression had shorter overall survival. Treatment with abemaciclib or palbociclib at 100 nM significantly decreased cell proliferation in all cell models evaluated. Both CDK4/6 inhibitors significantly induced G1 cell cycle arrest, thereby increasing cell senescence and increased the expression of interferon signalling pathway and tumour antigen presentation process in culture models of MPM. In vivo preclinical studies showed that palbociclib significantly reduced tumour growth and prolonged overall survival using distinct xenograft models of MPM implanted in athymic mice. Conclusions Treatment of MPM with CDK4/6 inhibitors decreased cell proliferation, mainly by promoting cell cycle arrest at G1 and by induction of cell senescence. Our preclinical studies provide evidence for evaluating CDK4/6 inhibitors in the clinic for the treatment of MPM.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 692/4017 / 692/4028/67/1641 / Aged / Aminopyridines - administration & dosage / Aminopyridines - pharmacology / Animals / Antigen presentation / Antitumor activity / Benzimidazoles - administration & dosage / Benzimidazoles - pharmacology / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cell culture / Cell cycle / Cell growth / Cell Line, Tumor / Cell proliferation / Cell Proliferation - drug effects / Cell Survival - drug effects / Chemotherapy / Cyclin-dependent kinase 4 / Cyclin-Dependent Kinase 4 - genetics / Cyclin-Dependent Kinase 4 - metabolism / Cyclin-Dependent Kinase 6 - genetics / Cyclin-Dependent Kinase 6 - metabolism / Drug Resistance / Epidemiology / Female / Gene Expression Regulation, Neoplastic - drug effects / Humans / Immunotherapy / Interferon / Male / Mesothelioma / Mesothelioma, Malignant - drug therapy / Mesothelioma, Malignant - genetics / Mesothelioma, Malignant - metabolism / Mice / Molecular Medicine / Oncology / Patients / Piperazines - administration & dosage / Piperazines - pharmacology / Protein Kinase Inhibitors - administration & dosage / Protein Kinase Inhibitors - pharmacology / Pyridines - administration & dosage / Pyridines - pharmacology / Senescence / Signal transduction / Transcriptomics / Tumors / Up-Regulation - drug effects / Xenograft Model Antitumor Assays / Xenografts