Overcoming Breast Cancer Resistance through Targeted Protein Degradation and Next Generation Chimeras

Proteolysis-Targeting Chimeras (PROTACs) represent a paradigm shift from occupancy-driven inhibition to event-driven protein elimination in cancer therapy. By harnessing the ubiquitin-proteasome system, PROTACs catalytically degrade disease-driving proteins. In breast cancer, the most commonly diagnosed cancer in women globally, PROTAC technology has advanced rapidly from preclinical concept to clinical validation. This review systematically evaluates PROTAC development across multiple therapeutic targets in breast cancer, including estrogen receptor α (ERα), human epidermal growth factor receptor 2 (HER2), bromodomain-containing protein 4 (BRD4), poly(ADP-ribose) polymerase 1 (PARP1), cyclin-dependent kinases 4/6 (CDK4/6), and enhancer of zeste homolog 2 (EZH2). We discuss structure-guided design principles, ternary complex formation mechanisms, and pharmacokinetic/pharmacodynamic profiles. Notably, the ERα degrader vepdegestrant (ARV-471) achieved positive Phase III results in the VERITAC-2 trial, demonstrating significant progression-free survival benefit in ESR1-mutant ER+/HER2- breast cancer, marking a milestone for PROTAC clinical translation. Preclinical studies of HER2, BRD4, and other PROTACs show promising efficacy with DC50 values in the nanomolar range and superior tumor growth inhibition compared to conventional inhibitors. However, challenges remain in optimizing oral bioavailability, minimizing off-target effects, and overcoming resistance mechanisms including target protein loss and E3 ligase pathway alterations. Emerging technologies such as lysosome-targeting chimeras (LYTAC) and next-generation E3 ligases expand the druggable target space. With over 30 PROTACs currently in clinical trials across oncology, this review provides a comprehensive analysis of PROTAC applications in breast cancer and outlines future directions for precision medicine.