Elisabet Aliagas1, Ania Alay1,2, Maria Martínez-Iniesta3, Miguel Hernández-Madrigal1, David Cordero1,2,4, Mireia Gausachs1, Eva Pros5, Maria Saigí5, Sara Busacca6, Annabel J Sharkley7, Alan Dawson8, Ramón Palmero1,9, José C Ruffinelli9, Susana Padrones10, Samantha Aso10, Ignacio Escobar11, Ricard Ramos11, Roger Llatjós12, August Vidal12, Eduard Dorca12, Mar Varela12, Montse Sánchez-Céspedes5, Dean Fennell6,13, Cristina Muñoz-Pinedo1, Alberto Villanueva3, Xavi Solé1,2,4, Ernest Nadal14,15,16. 1. Preclinical and Experimental Research in Thoracic Tumors (PrETT) group. Oncobell Program. Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat (Barcelona), Barcelona, Spain. 2. Unit of Bioinformatics for Precision Oncology, Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat (Barcelona), Barcelona, Spain. 3. Chemoresistance group. Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat (Barcelona), Barcelona, Spain. 4. Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Barcelona, Spain. 5. Cancer Genetics Group, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Badalona, Barcelona, Spain. 6. Department of Genetics and Genome Biology, Leicester Cancer Research Centre, University of Leicester, Leicester, UK. 7. University of Sheffield Teaching Hospitals, Sheffield, UK. 8. Department of Thoracic Surgery, Glenfield Hospital, Leicester, UK. 9. Department of Medical Oncology, Catalan Institute of Oncology, L'Hospitalet de Llobregat (Barcelona), Barcelona, Spain. 10. Department of Respiratory Medicine, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat (Barcelona), Barcelona, Spain. 11. Department of Thoracic Surgery, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat (Barcelona), Barcelona, Spain. 12. Department of Pathology, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat (Barcelona), Barcelona, Spain. 13. Mesothelioma Research Programme, Department of Genetics and Genome Biology, University of Leicester, Leicester, UK. 14. Preclinical and Experimental Research in Thoracic Tumors (PrETT) group. Oncobell Program. Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat (Barcelona), Barcelona, Spain. esnadal@iconcologia.net. 15. Department of Medical Oncology, Catalan Institute of Oncology, L'Hospitalet de Llobregat (Barcelona), Barcelona, Spain. esnadal@iconcologia.net. 16. Department of Clinical Sciences, School of Medicine and Health Sciences, Universitat de Barcelona, L'Hospitalet del Llobregat (Barcelona), Campus Bellvitge, Barcelona, Spain. esnadal@iconcologia.net.
Abstract
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.
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.
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