MCF-7 cells long-term treated with Fulv plus Abema acquired ESR1 Y537S mutation and exhibited defective RSR and DDR

ESR1 mutations are the leading cause of endocrine therapy resistance and progression in ER-positive metastatic breast cancer. ESR1 mutations are detected in ~50% of metastatic breast cancer patients, and identification of effective targeted therapeutics are critically needed. Here, we identified enrichment of dysregulated replication stress and DNA damage responses in multiple ESR1 mutant models. Long-term treatment with endocrine therapy Fulvestrant plus the CDK4/6 inhibitor abemaciclib led to the emergence of a Y537S ESR1 mutation in a cell line, which exhibited dysregulation of replication stress response, enhanced DNA damage response, and synergistic responses to inhibitors of these pathways. Overall design: RNA-Seq profiling of the MCF-7 parental wild-type ESR1, Abemaciclib resistant MCF-7 with wild-type ESR1, fulvestrant and Abemaciclib reistant MCF-7 treated for 8 months with 3% Y537S ESR1, and fulvestrant and Abemaciclib resistant MCF-7 cells treated for 12 months with 30% Y537S ESR1.