Abstract PS1-07-11: Vepdegestrant Overcomes Endocrine and CDK4/6i Resistance to Enhance Radiosensitivity in ESR1 mutant ER+ Breast Cancer

Abstract Background: Resistance to endocrine therapy and CDK4/6 inhibitors (CDK4/6i) poses a major barrier to effective management of estrogen receptor-positive (ER+) breast cancer, especially tumors harboring activating ESR1 mutations such as Y537S. Previous work by our group has demonstrated that combining ER inhibition with CDK4/6i significantly enhances radiosensitivity in ER+ breast cancer models. Given this synergy, we hypothesized that targeted ER degradation using Vepdegestrant (ARV-471), a potent PROTAC-based ER degrader, would further augment radiosensitization in models resistant to CDK4/6 inhibition and endocrine therapy. Methods:We evaluated ARV-471 in ER+ breast cancer cell lines, including wild-type MCF-7, tamoxifen-resistant ESR1 Y537S-mutant MCF-7, and CDK4/6i-resistant variants, with and without radiation. Radiosensitization was quantified using clonogenic survival assays. Mechanistic effects on DNA double-strand break repair were assessed through non-homologous end joining (NHEJ) and homologous recombination (HR) reporter assays. Results: ARV-471 induced potent, dose-dependent (5 nM – 100 nM) ERα degradation across all cell lines, including tamoxifen-resistant and CDK4/6i-resistant variants. ARV-471 treatment (3 nM) significantly enhanced radiosensitivity (radiation enhancement ratio (rER) 1.23 – 1.35, p-value