In this study, we investigate the efficacy of pharmacological cyclin D-dependent kinase (CDK) 4/6 inhibition and explore the relevance of p16 as predictors of susceptibility to CDK 4/6 therapy.<h4>Materials and methods</h4>CDK 4/6 inhibitors were evaluated in native and FOLFOX- or ribociclib-resistant CRC, hepatocellular carcinoma (HCC), and breast cancer (BC) cell lines using viability, colony formation, and flow cytometry (FC)-based assays. Here, CDKN2A is linked to hepatocellular carcinoma.