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

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

Nat Cell Biol. 2021 Nov;23(11):1187-1198. doi: 10.1038/s41556-021-00781-z. Epub 2021 Nov 4.

Authors

Yihao Li^#^{1

2}, Xintao Qiu^#^{1

2}, Xiaoqing Wang^{1

2}, Hui Liu³, Renee C Geck³, Alok K Tewari^{1

2}, Tengfei Xiao^{1

2}, Alba Font-Tello^{1

2}, Klothilda Lim^{1

2}, Kristen L Jones⁴, Murry Morrow⁴, Raga Vadhi^{1

2}, Pei-Lun Kao^{5

6}, Aliya Jaber^{5

6}, Smitha Yerrum^{5

6}, Yingtian Xie^{1

2}, Kin-Hoe Chow^{5

6}, Paloma Cejas^{1

2}, Quang-Dé Nguyen⁴, Henry W Long^{1

2}, X Shirley Liu^{2

7}, Alex Toker^{3

8}, Myles Brown^{9

10

11}

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
² Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
³ Department of Pathology, and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
⁴ Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, Boston, MA, USA.
⁵ Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
⁶ Center for Patient Derived Models, Dana-Farber Cancer Institute, Boston, MA, USA.
⁷ Department of Data Science, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁸ Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.
⁹ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. myles_brown@dfci.harvard.edu.
¹⁰ Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA. myles_brown@dfci.harvard.edu.
¹¹ Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA. myles_brown@dfci.harvard.edu.

^# Contributed equally.

PMID: 34737445
DOI: 10.1038/s41556-021-00781-z

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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
Signal Transduction
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*

Substances

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