Abstract B010: Drug tolerant persister cancer cells escape therapy-induced senescence

Abstract

Triple-negative breast cancer (TNBC) accounts for 15% of breast cancers and is the most aggressive subtype lacking precision oncology therapeutic strategies. Standard-of-care is predominantly chemotherapy in the neoadjuvant setting (NACT). Despite good responses, ∼40% of TNBC patients develop resistance and present residual disease at surgery. Overcoming resistance and implementing better therapeutic options is critical. Our objectives are to develop targeting opportunities for drug tolerant persister (DTP) cells which underlie residual disease. Using our unique biobank of patient derived xenografts from treatment naive as well as NACT resistant TNBC, we developed longitudinal in vivo models of residual and relapse tumors to standard-of-care therapy. Transcriptomic analysis revealed transient metabolic changes such as oxidative phosphorylation, starvation and autophagy, associated with hallmarks of senescence at residual disease. We demonstrated that therapy-induced senescent cells in vitro can escape cell cycle arrest and resume proliferation through autophagy. Interfering with autophagy impairs redox balance, promotes ferroptosis and delays tumor relapse. These results support that autophagy is a promising targetable vulnerability in TNBC residual disease. Citation Format: Anne-Marie Fortier, Jason Topolski, Gabriel Alzial, Anie Monast, Hellen Kuasne, Dongmei Zuo, Alain Pacis, Genevieve Deblois, Morag Park. Drug tolerant persister cancer cells escape therapy-induced senescence [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr B010.