Allele-Specific Chromatin Recruitment and Therapeutic Vulnerabilities of <i>ESR1</i> Activating Mutations

Abstract

Estrogen receptor (ER) ligand-binding domain mutations are found in up to 40% of patients with endocrine therapy resistant metastatic ER-positive (ER ) breast cancer. We investigated the chromatin recruitment, transcriptional network and genetic vulnerabilities in breast cancer models harboring the most clinically relevant ER mutations. These ER mutations exhibit both ligand-independent functions that mimic estradiol bound wild type ER as well as allele-specific neomorphic properties that promote a pro-metastatic phenotype. The transcriptomes of a large set of ER metastatic biopsies validated the mutant allele-specific programs identified in the models. The mutant-selective ER cistrome is FOXA1 independent and mediates the allele-specific transcriptional program. Genome-wide CRISPR knockout screens identified genes that are essential for the ligand independent growth driven by the ER mutants including mutantselective synthetic vulnerabilities. These studies provide new insights into the mechanism of endocrine therapy resistance engendered by ER ligand binding domain mutations including clinically relevant allele-specific differences and potential new therapeutic targets.