Figure 1. Model for palbociclib‐induced senescence.

Palbociclib has two pro‐senescence effects on cancer cells. Through inhibition of CDK4 and CDK6, the tumour suppressor RB1 is maintained in an active hypophosphorylated form, which arrests cells in the G1 phase of the cell cycle. Palbociclib also activates the proteasome through decreasing its binding to the proteasome inhibitor ECM29. This in turn causes stress resulting from increased proteolysis. Together, these two effects cause a senescence response in cancer cells.