Combined Inhibition of CDK4/6 and PI3K/AKT/mTOR Pathways Induces a Synergistic Anti-Tumor Effect in Malignant Pleural Mesothelioma Cells

• DOI: 10.1016/j.neo.2017.05.003
• Publication Date: 2017-07-11T08:56:27Z
• Authors: Mara A. Bonelli; Graziana Digiacomo; Claudia Fumarola; Roberta Alfieri; Federico Quaini; Angela Falco; Denise Madeddu; Silvia La Monica; Daniele Cretella; Andrea Ravelli; Paola Ulivi; Michela Tebaldi; Daniele Calistri; Angelo Delmonte; Luca Ampollini; Paolo Carbognani; Marcello Tiseo; Andrea Cavazzoni; Pier Giorgio Petr...
• Keywords: Palbociclib; Cyclin-dependent kinase 6

Malignant pleural mesothelioma (MPM) is a progressive malignancy associated to the exposure of asbestos fibers. The most frequently inactivated tumor suppressor gene in MPM CDKN2A/ARF, encoding for cell cycle inhibitors p16INK4a and p14ARF, deleted about 70% cases. Considering high frequency alterations this gene, we tested cells efficacy palbociclib (PD-0332991), highly selective inhibitor cyclin-dependent kinase (CDK) 4/6. analyses were performed on panel lines two primary culture from effusion patients with MPM. All lines, as well cultures, sensitive significant blockade G0/G1 phase acquisition senescent phenotype. Palbociclib reduced phosphorylation levels CDK6 Rb, expression myc concomitant increased AKT. Based these results, combination PI3K NVP-BEZ235 or NVP-BYL719. After treatment, sequential association synergistically hampered proliferation strongly percentage cells. In addition, AKT activation was repressed while p53 p21 up-regulated. Interestingly, cycles drug administration produced irreversible growth arrest phenotype that maintained even after withdrawal. These findings suggest may represent valuable therapeutic option treatment