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

Autor: Xiaoqing Wang, Raga Vadhi, Pei-Lun Kao, Alok K. Tewari, Kin-Hoe Chow, Renee C. Geck, Aliya Jaber, X. Shirley Liu, Alba Font-Tello, Tengfei Xiao, Paloma Cejas, Klothilda Lim, Hui Liu, Xintao Qiu, Murry Morrow, Henry W. Long, Yingtian Xie, Smitha Yerrum, Yihao Li, Quang-Dé Nguyen, Alex Toker, Myles Brown, Kristen L Jones
Rok vydání: 2021
Předmět:
Chromosomal Proteins
Non-Histone
FGFR Inhibition
Antineoplastic Agents
Triple Negative Breast Neoplasms
mTORC1
Mechanistic Target of Rapamycin Complex 1
Epigenesis
Genetic
Downregulation and upregulation
Cell Line
Tumor
Antineoplastic Combined Chemotherapy Protocols
Humans
Molecular Targeted Therapy
Epigenetics
Amino Acids
Chemistry
Phenylurea Compounds
DNA Helicases
Nuclear Proteins
Drug Synergism
YAP-Signaling Proteins
Cell Biology
Chromatin Assembly and Disassembly
Receptors
Fibroblast Growth Factor
Xenograft Model Antitumor Assays
SWI/SNF
Cell biology
Chromatin
Gene Expression Regulation
Neoplastic
Pyrimidines
Drug Resistance
Neoplasm
Fibroblast growth factor receptor
Multiprotein Complexes
Cancer cell
Female
biological phenomena
cell phenomena
and immunity
Signal Transduction
Transcription Factors
Zdroj: Nature Cell Biology. 23:1187-1198
ISSN: 1476-4679
1465-7392
Popis: 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. Li et al. define an adaptive resistance mechanism against FGFR inhibitor treatment in breast cancer attributed to loss of BRG1 chromatin recruitment, reactivation of YAP-dependent enhancers and upregulation of amino acid-induced mTORC1 activity.
Databáze: OpenAIRE
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