FGFR inhibitor mediated dismissal of SWI/SNF complexes from YAP-dependent enhancers induces therapeutic resistance in triple negative breast cancer

Abstract How cancer cells adapt to evade the therapeutic effects of drugs targeting oncogenic drivers is poorly understood. Here we report an epigenetic mechanism leading to the adaptive resistance of triple-negative breast cancer (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. Collectively, these findings reveal a novel feedback loop involving an epigenetic state transition and metabolic reprogramming that leads to adaptive therapeutic resistance and provide new therapeutic strategies to overcome this mechanism of resistance. Citation Format: Yihao Li, Xintao Qiu, Xiaoqing Wang, Hui Liu, Renee Geck Geck, Alok Tewari, Kin-Hoe Chow, Tengfei Xiao, Paloma Cejas, Quang-Dé Nguyen, Henry Long, Shirley X Liu, Alex Toker, Myles Brown. FGFR inhibitor mediated dismissal of SWI/SNF complexes from YAP-dependent enhancers induces therapeutic resistance in triple negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-01-04.