Inhibitors of cyclin-dependent kinase 4 (CDK4) and CDK6, such as palbociclib, have significantly improved progression-free survival of several breast cancer types, such as hormone receptor-positive, HER2-negative luminal breast cancers, with about 40% being unresponsive or refractory to therapy; the main cause of resistance is the selection of mutant clones in the target oncoprotein.