Abstract 1400: SWI/SNF chromatin remodeling complex regulation of YAP-dependent enhancers drives therapeutic resistance in triple-negative breast cancer

Abstract

Abstract Outcomes for patients with triple negative breast cancer (TNBC) remain poor despite significant advances in the treatment of other breast cancer subtypes. We report an epigenetic mechanism leading to the adaptive resistance of TNBC to fibroblast growth factor receptor (FGFR) inhibitors. Prolonged FGFR inhibition suppresses the function of BRG1-dependent chromatin remodeling leading to an epigenetic state that derepresses YAP-associated enhancers. These chromatin changes induce the expression of several amino acid transporters resulting in increased intracellular levels of specific amino acids that reactivate mTORC1. Consistent with this mechanism, addition of mTORC1 or YAP inhibitors to FGFR blockade synergistically attenuated the growth of TNBC patient-derived xenografts (PDX) models. Treatment-induced YAP/TEAD accessible chromatin was observed in a subpopulation of PDX cells by single cell analysis of accessible chromatin. Thus, combinatorial therapies based on the YAP and mTORC1 dependent feedback loop have the potential to improve the efficacy of FGFR inhibitors in TNBC. Citation Format: Yihao Li, Xintao Qiu, Hui Liu, Xiaoqing Wang, Renee C. Geck, Alok Tewari, Kin-Hoe Chow, Paloma Cejas, Quang-Dé Nguyen, Henry Long, Shirley X. Liu, Alex Toker, Myles Brown. SWI/SNF chromatin remodeling complex regulation of YAP-dependent enhancers drives therapeutic resistance in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1400.