In a separate AML study, CDK4 sensitivity to both ATP and palbociclib binding was reduced in the presence of high p16INK4a levels.80 Collectively, these studies suggest a further mechanism of ATP-competitive inhibitor resistance: Increased INK4 expression generates CDK4/6-cyclin D-INK4 complexes that retain sufficient kinase activity to drive cell cycle progression but escape orthosteric small molecule inhibition. Here, CDK4 is linked to acute myeloid leukemia.