The cyclin D1/CDK4 axis mediates the resistance to trastuzumab in HER2-positive breast cancer models, which can be reverted by CDK4/6 inhibition10, providing a solid rationale for simultaneous targeting HER2, ER, and CDK4/6 in HR-positive, HER2-positive breast cancer. The gene discussed is CDK4; the disease is breast carcinoma.