The CDK4 and 6 pathways can mediate resistance to HER2-targeted agents, and the activity of CDK4/6 inhibitors on luminal HER2-expressing cells is well established [99], providing a basis for clinical evaluation of combinations of CDK4/6 inhibitors with HER2-targeted agents in ER-positive HER2-positive breast cancer. The gene discussed is ERBB2; the disease is breast cancer.