Single cell multiomics reveals evolutionary and epigenomic trajectories of PARP inhibitor resistance in BRCA mutant TNBC

Poly (ADP-ribose) polymerase (PARP) inhibitors show marked efficacy in BRCA-mutant triple-negative breast cancer (TNBC), yet nearly half of patients treated with neoadjuvant PARP inhibition fail to achieve pathological complete response, revealing a major obstacle of intrinsic and therapy-induced resistance. To dissect the mechanisms enabling tumor persistence, we performed integrated single-cell transcriptomic and chromatin-accessibility profiling on paired pre- and post-treatment patient-derived xenograft (PDX) samples from a Phase II trial of single-agent talazoparib in germline BRCA1/2-mutant TNBC. This multi-omic framework resolved therapy driven remodeling of tumor ecosystems and gene regulatory circuitry at cellular resolution. We uncover that rare, pre-existing homologous-recombination proficient subclones selectively expand under PARP inhibition and act as reservoirs for residual disease. Network-level integration of expression and chromatin accessibility further revealed extensive epigenomic rewiring in therapy-induced resistant populations, characterized by elevated DNA-repair activity, metabolic reprogramming, and activation of survival pathways. We also identify candidate master transcription factors that likely orchestrate these resistance-associated regulatory states. Collectively, our findings delineate the evolutionary routes by which BRCA-mutant TNBC evades PARP inhibition and highlight how both baseline HRR-proficient subpopulations and transcription factor driven chromatin reprogramming shape therapeutic outcome. These insights nominate actionable vulnerabilities that may be exploited to prevent or overcome resistance and enhance the durability of PARP-inhibitor therapy.