| Literature DB >> 34737445 |
Yihao Li1,2, Xintao Qiu1,2, Xiaoqing Wang1,2, Hui Liu3, Renee C Geck3, Alok K Tewari1,2, Tengfei Xiao1,2, Alba Font-Tello1,2, Klothilda Lim1,2, Kristen L Jones4, Murry Morrow4, Raga Vadhi1,2, Pei-Lun Kao5,6, Aliya Jaber5,6, Smitha Yerrum5,6, Yingtian Xie1,2, Kin-Hoe Chow5,6, Paloma Cejas1,2, Quang-Dé Nguyen4, Henry W Long1,2, X Shirley Liu2,7, Alex Toker3,8, Myles Brown9,10,11.
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 remodelling, 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 xenograft models. Collectively, these findings reveal a feedback loop involving an epigenetic state transition and metabolic reprogramming that leads to adaptive therapeutic resistance and provides potential therapeutic strategies to overcome this mechanism of resistance.Entities:
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Year: 2021 PMID： 34737445 DOI： 10.1038/s41556-021-00781-z
Source DB: PubMed Journal: Nat Cell Biol ISSN： 1465-7392 Impact factor: 28.824