CDK4 and melanoma: Notably, S477/T479 is a CDK2-dependent phosphorylation site.[31] PDXs in CDK4/6i resistant melanoma often shows activation of the PI3K -Akt pathway, inhibiting this pathway to improve CDK4/6i response in a p21-dependent manner.[19] A melanoma model showed that the PI3K/Akt pathway has been shown to mediate CDK4/6i resistance by inhibiting P21.[48]