Many human tumors acquire alterations which can lead to the activation of cyclin-dependent kinases (CDKs). These alterations include mutations that directly activate CDK4/6; gene amplifications, which increase expression of various protein activators such as D-type cyclins; as well as genetic losses, which reduce expression of protein inhibitors such as p16. These various mechanisms as well as loss of retinoblastoma (Rb) can lead to an enhanced proliferative potential by decreasing dependency on external growth factors and mitogenic signaling pathways, which are required to stimulate growth under normal conditions.^2,3

Abemaciclib has been shown in vitro to be a selective ATP-competitive inhibitor of CDK4/6 kinase activity that prevents the phosphorylation and subsequent inactivation of the Rb tumor suppressor protein, thereby inducing G1 cell-cycle arrest and inhibition of cell proliferation.^4,5