Journal Article

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

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

2021

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38 / 631/67/1059/2326 / 631/67/1347 / 631/80/86/2368 / 82/58 / Amino acids / Amino Acids - metabolism / Antineoplastic Agents - pharmacology / Antineoplastic Combined Chemotherapy Protocols - pharmacology / Binding proteins / Biological response modifiers / Biomedical and Life Sciences / Breast cancer / BRG1 protein / Cancer / Cancer Research / Cell Biology / Cell Line, Tumor / Chromatin Assembly and Disassembly / Chromatin remodeling / Chromosomal Proteins, Non-Histone - genetics / Chromosomal Proteins, Non-Histone - metabolism / Complications and side effects / Developmental Biology / DNA Helicases - genetics / DNA Helicases - metabolism / Drug delivery / Drug resistance / Drug Resistance, Neoplasm - genetics / Drug Synergism / Drug therapy / Epigenesis, Genetic / Epigenetic inheritance / Epigenetics / Feedback loops / Female / Fibroblast growth factor receptors / Gene Expression Regulation, Neoplastic / Genetic aspects / Growth factors / Health aspects / Humans / Intracellular levels / Life Sciences / Mechanistic Target of Rapamycin Complex 1 - antagonists & inhibitors / Mechanistic Target of Rapamycin Complex 1 - genetics / Mechanistic Target of Rapamycin Complex 1 - metabolism / Molecular Targeted Therapy / Multiprotein Complexes / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Oncology, Experimental / Phenylurea Compounds - pharmacology / Pyrimidines - pharmacology / Receptors, Fibroblast Growth Factor - antagonists & inhibitors / Receptors, Fibroblast Growth Factor - metabolism / Signal Transduction / Stem Cells / Transcription factors / Transcription Factors - genetics / Transcription Factors - metabolism / Triple Negative Breast Neoplasms - drug therapy / Triple Negative Breast Neoplasms - genetics / Triple Negative Breast Neoplasms - metabolism / Triple Negative Breast Neoplasms - pathology / Xenograft Model Antitumor Assays / Xenografts / Xenotransplantation / YAP-Signaling Proteins - antagonists & inhibitors / YAP-Signaling Proteins - genetics / YAP-Signaling Proteins - metabolism / Yes-associated protein