Carcinogenesis of malignant pleural mesothelioma (MPM) is strictly associated with chronic exposure of mesothelial cells from the pleura to asbestos fibers and MPM incidence is expected to peak in the next years. Extensive genome analyses of patient-derived MPM tumors revealed that the most frequent mutational event involves the inactivation of the CDKN2A gene that encodes for the cell cycle inhibitors p16$^{\rm INK4a}$ and p14$^{\rm ARF}$ with consequent constitutive activation of CDK4/6 - cyclin D complexes. Therefore, inhibition of the latter complexes may represent a new option for the treatment of MPM patients. However, despite the efficacy of the specific CDK4/6 inhibitor palbociclib in blocking MPM cell proliferation, acquired resistance inevitably occurs. Herein, palbocilib-resistant clones isolated after stepwise exposure of MSTO-211H cells to gradually increasing drug concentrations, showed a reduction in Rb protein levels as well as in the cell cycle inhibitor p21$^{\rm waf1}$, accompanied by increased phosphorylation of AKT and p70S6K. Simultaneous treatment of resistant clones with both palbociclib and specific PI3K/AKT/mTOR inhibitors produced an additive effect in terms of reduction in cell growth, without any signs of senescence but with increased cell death. In MSTO-211H sensitive cells, this combination drug treatment significantly delayed the adaptation to palbociclib, suggesting that this treatment approach may prevent or at least retard the emergence of palbociclib resistance. Collectively, these results suggest that the combination of palbociclib with PI3K/AKT/mTOR inhibitors may overcome the acquisition of resistance to palbociclib treatment and could represent a potential therapeutic approach to treat cancers with acquired resistance to CDK4/6 inhibitors in the presence of activation of the AKT/mTOR signaling pathway.