The potential of PI3K/mTOR monotherapy to reverse resistance to CDK4/6-based therapies, in the absence of continued CDK4/6-endocrine-based therapies, was evaluated in ER+/HER2− breast cancer cell line xenograft models conditioned to acquire resistance to palbociclib and then palbociclib/fulvestrant therapy: HCC1500 (PIK3CA wild-type) and MCF7 (PIK3CA-mutant). The gene discussed is ESR1; the disease is breast carcinoma.