Before translating the preclinical findings on the utility of CDK4/6is for CCA and PDAC into clinical trials, it is important to decipher the molecular mechanisms of CDK4/6is action and their effects on cell cycle arrest in a cancer-specific context, taking into account the effects of CDK4/6 inhibition on the tumoral microenvironment and angiogenesis. Here, CDK4 is linked to cancer.