INHIBITION OF CYCLIN-DEPENDENT PROTEIN KINASES AS A POTENTIAL NEW THERAPEUTIC STRATEGY FOR THE TREATMENT OF MALIGNANT PLEURAL MESOTHELIOMA

Direct or indirect exposure to asbestos fibers can cause various respiratory pathologies such as asbestosis or pleural effusion, up to more serious pathologies, even tumors such as malignant pleural mesothelioma (MPM). MPM is a highly aggressive tumor for which there is still no effective therapeutic strategy today and, despite the use of asbestos being banned in many western countries, unfortunately an increase in incidence is still estimated. This is due both to the long clinical latency that characterizes the development of MPM (about 40 years), and to the environmental persistence of materials containing asbestos. To date, MPM still represents a therapeutic challenge, and therefore, the identification of new and effective therapies is urgently needed. In recent years various approaches have been tested in the preclinical phase by the group where I carried out my thesis activity, such as the inhibition of the oncogenic kinase SRC, or the reactivation of p53, both capable of inducing cell death both in MPM lines than in in vivo experiments. More recently they observed that reactivation of the RBL2/p130 tumor suppressor was also able to induce apoptosis in MPM cell lines. These data suggested that acting by restoring the function of retinoblastoma family proteins could be an effective strategy for this tumor. The aim of my thesis project was to verify whether the inhibition of the cyclin-cycline kinase dependent complexes, more specifically using the cyclin dependent kinase (CDK) inhibitor abemaciclib, was able to act on the pocket proteins, reactivating their tumor suppressor potential.