Many Ways to the Cell Cycle Exit after Inhibition of CDK4/6.

Cyclin-dependent kinases (CDKs) are master regulators of proliferation, and therefore they represent attractive targets for cancer therapy. Deve-lopment of selective CDK4/6 inhibitors including palbociclib revolutionized the treatment of advanced HR+/HER2- breast cancer. Inhibition of CDK4/6 leads to cell cycle arrest in G0/G1 phase and eventually to a permanent cell cycle exit called senescence. One of the main features of the senescence is an increased cell size. For many years, it was believed that the non-dividing cells simply continue to grow and as a result, they become excessively large. There is now emerging evidence that the increased cell size is a cause rather than consequence of the cell cycle arrest. This review aims to summarize recent advances in our understanding of senescence induction, in particular that resulting from treatment with CDK4/6 inhibitors.