Defective DNA Damage Response Is a Targetable Therapeutic Vulnerability in ESR1-Mutant Breast Cancer.

ESR1 mutations are the leading cause of endocrine therapy resistance and progression in estrogen receptor (ER)-positive metastatic breast cancer. ESR1 mutations are detected in ∼50% of patients with metastatic breast cancer, and identification of effective targeted therapeutics is critically needed. In this study, we identified enrichment of dysregulated replication stress and DNA damage responses in multiple ESR1-mutant models. Targeting the replication stress response utilizing checkpoint inhibition in combination with PARP inhibition synergistically suppressed growth, induced cell cycle arrest, and attenuated DNA replication. PARP inhibition blocked metastatic dissemination in vivo and reduced both PARP1 and ER-regulated protein expression. PARP trapping by olaparib treatment with or without endocrine therapy resulted in a significant increase in colocalized DNA-bound PARP1 and ER protein in ESR1-mutant cells, indicating ER-PARP1 coregulation in ESR1-mutant breast cancer. Long-term treatment with endocrine therapy plus the CDK4/6 inhibitor abemaciclib led to the emergence of a ESR1Y537S mutation in a cell line, which exhibited dysregulation of replication stress response, enhanced DNA damage response, and synergistic responses to inhibitors of these pathways. PARP inhibition also synergized with clinically relevant endocrine therapy in ESR1-mutant models, reducing tumor growth both ex vivo and in vivo. Together, these results identify replication stress and DNA damage responses as key dysregulated pathways in ESR1-mutant breast cancer with significant clinical potential for PARP inhibition in this metastatic breast cancer subset. SIGNIFICANCE: ESR1-mutant breast cancer exhibits enriched replication stress and DNA damage, creating a therapeutic vulnerability to PARP inhibition in ER+ breast cancer without genomic homologous recombination defects.