Nevertheless, our data suggest that the approved treatment with fulvestrant combined with a CDK4/6i efficaciously inhibits the growth of endocrine-sensitive and some endocrine-resistant breast cancer cells, but simultaneous inhibition of ER, CDK4/6, and AKT is required to durably suppress the growth of most the endocrine-resistant cells of different breast cancer models. The gene discussed is CDK4; the disease is breast cancer.