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FGFR inhibitor mediated dismissal of SWI/SNF complexes from YAP-dependent enhancers induces adaptive therapeutic resistance

By Yihao Li, Xintao Qiu, Xiaoqing Wang, Hui Liu, Renee C. Geck, Alok K. Tewari, Tengfei Xiao, Alba Font-Tello, Klothilda Lim, Kristen L. Jones, Murry Morrow, Raga Vadhi, Pei-Lun Kao, Aliya Jaber, Smitha Yerrum, Yingtian Xie, Kin-Hoe Chow, Paloma Cejas, Quang-Dé Nguyen, Henry W Long, X. Shirley Liu, Alex Toker, Myles Brown

Posted 02 Mar 2021
bioRxiv DOI: 10.1101/2021.03.02.433446

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. Collectively, these findings reveal a novel feedback loop involving an epigenetic state transition and metabolic reprogramming that leads to adaptive therapeutic resistance.

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