British journal of cancer · 2021
Efficacy of CDK4/6 inhibitors in preclinical models of malignant pleural mesothelioma.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Aliagas Elisabet, Alay Ania, Martínez-Iniesta Maria, Hernández-Madrigal Miguel, Cordero David, Gausachs Mireia, Pros Eva, Saigí Maria, Busacca Sara, Sharkley Annabel J, Dawson Alan, Palmero Ramón, Ruffinelli José C, Padrones Susana, Aso Samantha, Escobar Ignacio, Ramos Ricard, Llatjós Roger, Vidal August, Dorca Eduard, Varela Mar, Sánchez-Céspedes Montse, Fennell Dean, Muñoz-Pinedo Cristina, Villanueva Alberto, Solé Xavi, Nadal Ernest
Аннотация
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.
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.
Предметные рубрики MeSH
AgedAminopyridinesAnimalsBenzimidazolesCell Line, TumorCell ProliferationCell SurvivalCyclin-Dependent Kinase 4Cyclin-Dependent Kinase 6FemaleGene Expression Regulation, NeoplasticHumansMaleMesothelioma, MalignantMicePiperazinesProtein Kinase InhibitorsPyridinesUp-RegulationXenograft Model Antitumor Assays