Here, we first aimed to assess the efficacy of first-generation CDK4/6i, ribociclib, palbociclib, and abemaciclib, on our panel of DPM cell lines characterized by the loss of CDKN2A. As expected, all CDK4/6i showed efficacy in reducing DPM cell viability, whereas normal immortalized MET-5A mesothelial cells were not affected by palbociclib at the range of concentrations tested or affected by abemaciclib and ribociclib at higher doses compared to those inhibiting cancer cells. This evidence concerns the gene CDK4 and cancer.