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

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

doi:10.1038/s41556-021-00781-z

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

Journal article

Peer reviewed

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

Yihao Li, Xintao Qiu, Xiaoqing Wang, Hui Liu, Renee C Geck, Alok K Tewari, Tengfei Xiao, Alba Font-Tello, Klothilda Lim, Kristen L Jones, …

Nature cell biology, Vol.23(11), pp.1187-1198

11/01/2021

DOI: https://doi.org/10.1038/s41556-021-00781-z

PMID: 34737445

Abstract

Amino Acids - metabolism

Antineoplastic Agents - pharmacology

Antineoplastic Combined Chemotherapy Protocols - pharmacology

Cell Line, Tumor

Chromatin Assembly and Disassembly

Chromosomal Proteins, Non-Histone - genetics

Chromosomal Proteins, Non-Histone - metabolism

DNA Helicases - genetics

DNA Helicases - metabolism

Drug Resistance, Neoplasm - genetics

Drug Synergism

Epigenesis, Genetic

Female

Gene Expression Regulation, Neoplastic

Humans

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

Phenylurea Compounds - pharmacology

Pyrimidines - pharmacology

Receptors, Fibroblast Growth Factor - antagonists & inhibitors

Receptors, Fibroblast Growth Factor - metabolism

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

YAP-Signaling Proteins - antagonists & inhibitors

YAP-Signaling Proteins - genetics

YAP-Signaling Proteins - metabolism

Signal Transduction

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.

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Title: FGFR-inhibitor-mediated dismissal of SWI/SNF complexes from YAP-dependent enhancers induces adaptive therapeutic resistance
Creators: Yihao Li - Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
Xintao Qiu
Xiaoqing Wang - Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
Hui Liu - Department of Pathology, and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Renee C Geck - Department of Pathology, and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Alok K Tewari - Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
Tengfei Xiao - Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
Alba Font-Tello - Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
Klothilda Lim - Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
Kristen L Jones - Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, Boston, MA, USA
Murry Morrow - Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, Boston, MA, USA
Raga Vadhi - Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
Pei-Lun Kao - Center for Patient Derived Models, Dana-Farber Cancer Institute, Boston, MA, USA
Aliya Jaber - Center for Patient Derived Models, Dana-Farber Cancer Institute, Boston, MA, USA
Smitha Yerrum - Center for Patient Derived Models, Dana-Farber Cancer Institute, Boston, MA, USA
Yingtian Xie - Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
Kin-Hoe Chow - Center for Patient Derived Models, Dana-Farber Cancer Institute, Boston, MA, USA
Paloma Cejas - Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
Quang-Dé Nguyen - Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, Boston, MA, USA
Henry W. Long - Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
X. Shirley Liu - Department of Data Science, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health, Boston, MA, USA
Alex Toker - Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA
Myles Brown - Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA. myles_brown@dfci.harvard.edu
Publication Details: Nature cell biology, Vol.23(11), pp.1187-1198
Identifiers: 9924285586501921
Academic Unit: Rabb School of Continuing Studies, Division of Graduate Professional Studies
Language: English
Resource Type: Journal article

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

Abstract

UN Sustainable Development Goals (SDGs)

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