Herein, we assessed the efficacy of the AKTi capivasertib, CDK4/6i palbociclib, and the ER degrader fulvestrant as single agents and in double and triple combinations in ER+MCF-7, T47D, and ZR-75-1 fulvestrant-resistant and fulvestrant-sensitive breast cancer cell models. This evidence concerns the gene CDK4 and breast carcinoma.