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

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

Journal

Nature cell biology
ISSN: 1476-4679
Titre abrégé: Nat Cell Biol
Pays: England
ID NLM: 100890575

Informations de publication

Date de publication:
11 2021
Historique:
received: 10 02 2021
accepted: 26 09 2021
pubmed: 6 11 2021
medline: 30 12 2021
entrez: 5 11 2021
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s41556-021-00781-z PMID: 34737445
pubmed: 34737445
doi: 10.1038/s41556-021-00781-z
pii: 10.1038/s41556-021-00781-z
doi:

Substances chimiques

Amino Acids 0
Antineoplastic Agents 0
Chromosomal Proteins, Non-Histone 0
Multiprotein Complexes 0
Nuclear Proteins 0
Phenylurea Compounds 0
Pyrimidines 0
Receptors, Fibroblast Growth Factor 0
Transcription Factors 0
YAP-Signaling Proteins 0
YAP1 protein, human 0
infigratinib A4055ME1VK
Mechanistic Target of Rapamycin Complex 1 EC 2.7.11.1
SMARCA4 protein, human EC 3.6.1.-
DNA Helicases EC 3.6.4.-

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

1187-1198

Commentaires et corrections

Type : CommentIn

Informations de copyright

© 2021. The Author(s), under exclusive licence to Springer Nature Limited.

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Auteurs

Yihao Li (Y)

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.

Xintao Qiu (X)

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
ORCID: 0000-0002-8560-7017

Xiaoqing Wang (X)

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
ORCID: 0000-0001-7476-8889

Hui Liu (H)

Department of Pathology, and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Renee C Geck (RC)

Department of Pathology, and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
ORCID: 0000-0001-7812-7675

Alok K Tewari (AK)

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
ORCID: 0000-0003-2617-7499

Tengfei Xiao (T)

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.

Alba Font-Tello (A)

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.

Klothilda Lim (K)

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.

Kristen L Jones (KL)

Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, Boston, MA, USA.

Murry Morrow (M)

Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, Boston, MA, USA.

Raga Vadhi (R)

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.

Pei-Lun Kao (PL)

Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Center for Patient Derived Models, Dana-Farber Cancer Institute, Boston, MA, USA.

Aliya Jaber (A)

Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Center for Patient Derived Models, Dana-Farber Cancer Institute, Boston, MA, USA.

Smitha Yerrum (S)

Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Center for Patient Derived Models, Dana-Farber Cancer Institute, Boston, MA, USA.

Yingtian Xie (Y)

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.

Kin-Hoe Chow (KH)

Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Center for Patient Derived Models, Dana-Farber Cancer Institute, Boston, MA, USA.

Paloma Cejas (P)

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.

Quang-Dé Nguyen (QD)

Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, Boston, MA, USA.
ORCID: 0000-0002-9043-4413

Henry W Long (HW)

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
ORCID: 0000-0001-6849-6629

X Shirley Liu (XS)

Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Data Science, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
ORCID: 0000-0003-4736-7339

Alex Toker (A)

Department of Pathology, and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.

Myles Brown (M)

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. myles_brown@dfci.harvard.edu.
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA. myles_brown@dfci.harvard.edu.
Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA. myles_brown@dfci.harvard.edu.
ORCID: 0000-0002-8213-1658

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Acides aminés › FGFR-inhibitor-mediated dismissal of SWI/SNF...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antinéoplasiques › FGFR-inhibitor-mediated dismissal of SWI/SNF...
questionsmedicales.fr › Thérapeutique › Traitement médicamenteux › Association de médicaments › Protocoles de polychimiothérapie antinéoplasique › FGFR-inhibitor-mediated dismissal of SWI/SNF...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › FGFR-inhibitor-mediated dismissal of SWI/SNF...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Assemblage et désassemblage de la chromatine › FGFR-inhibitor-mediated dismissal of SWI/SNF...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Protéines chromosomiques nonhistones › FGFR-inhibitor-mediated dismissal of SWI/SNF...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Isomerases › Helicase › FGFR-inhibitor-mediated dismissal of SWI/SNF...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Résistance aux substances › Résistance aux médicaments antinéoplasiques › FGFR-inhibitor-mediated dismissal of SWI/SNF...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Interactions médicamenteuses › Synergie des médicaments › FGFR-inhibitor-mediated dismissal of SWI/SNF...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Épigenèse génétique › FGFR-inhibitor-mediated dismissal of SWI/SNF...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes tumoraux › FGFR-inhibitor-mediated dismissal of SWI/SNF...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › FGFR-inhibitor-mediated dismissal of SWI/SNF...
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