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

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.

• Authors: 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
• Journal: Nature cell biology (Nat Cell Biol) Vol. 23 Issue 11 Pg. 1187-1198 (11 2021) ISSN: 1476-4679 [Electronic] England
• PMID: 34737445 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• Amino Acids
• Antineoplastic Agents
• Chromosomal Proteins, Non-Histone
• Multiprotein Complexes
• Nuclear Proteins
• Phenylurea Compounds
• Pyrimidines
• Receptors, Fibroblast Growth Factor
• Transcription Factors
• YAP-Signaling Proteins
• YAP1 protein, human
• infigratinib
• Mechanistic Target of Rapamycin Complex 1
• SMARCA4 protein, human
• DNA Helicases

Topics

• Amino Acids (metabolism)
• Antineoplastic Agents (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Cell Line, Tumor
• Chromatin Assembly and Disassembly
• Chromosomal Proteins, Non-Histone (genetics, metabolism)
• DNA Helicases (genetics, metabolism)
• Drug Resistance, Neoplasm (genetics)
• Drug Synergism
• Epigenesis, Genetic
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Mechanistic Target of Rapamycin Complex 1 (antagonists & inhibitors, genetics, metabolism)
• Molecular Targeted Therapy
• Multiprotein Complexes
• Nuclear Proteins (genetics, metabolism)
• Phenylurea Compounds (pharmacology)
• Pyrimidines (pharmacology)
• Receptors, Fibroblast Growth Factor (antagonists & inhibitors, metabolism)
• Signal Transduction
• Transcription Factors (genetics, metabolism)
• Triple Negative Breast Neoplasms (drug therapy, genetics, metabolism, pathology)
• Xenograft Model Antitumor Assays
• YAP-Signaling Proteins (antagonists & inhibitors, genetics, metabolism)