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Molecular Cancer Research

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Oncogenes and Tumor Suppressors

The FGFR1 V561M Gatekeeper Mutation Drives AZD4547 Resistance through STAT3 Activation and EMT

Molly R. Ryan, Christal D. Sohl, BeiBei Luo and Karen S. Anderson
Molly R. Ryan
Department of Pharmacology, Yale University, New Haven, Connecticut.
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Christal D. Sohl
Department of Pharmacology, Yale University, New Haven, Connecticut.
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BeiBei Luo
Department of Pharmacology, Yale University, New Haven, Connecticut.
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Karen S. Anderson
Department of Pharmacology, Yale University, New Haven, Connecticut.
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  • For correspondence: karen.anderson@yale.edu
DOI: 10.1158/1541-7786.MCR-18-0429 Published February 2019
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Abstract

FGFR1 has been implicated in numerous cancer types including squamous cell lung cancer, a subset of non–small cell lung cancer with a dismal 5-year survival rate. Small-molecule inhibitors targeting FGFR1 are currently in clinical trials, with AZD4547 being one of the furthest along; however, the development of drug resistance is a major challenge for targeted therapies. A prevalent mechanism of drug resistance in kinases occurs through mutation of the gatekeeper residue, V561M in FGFR1; however, mechanisms underlying V561M resistance to AZD4547 are not fully understood. Here, the cellular consequences of the V561M gatekeeper mutation were characterized, and it was found that although AZD4547 maintains nanomolar affinity for V561M FGFR1, based on in vitro binding assays, cells expressing V561M demonstrate dramatic resistance to AZD4547 driven by increased STAT3 activation downstream of V561M FGFR1. The data reveal that the V561M mutation biases cells toward a more mesenchymal phenotype, including increased levels of proliferation, migration, invasion, and anchorage-independent growth, which was confirmed using CyTOF, a novel single-cell analysis tool. Using shRNA knockdown, loss of STAT3 restored sensitivity of cancer cells expressing V561M FGFR1 to AZD4547. Thus, the data demonstrate that combination therapies including FGFR and STAT3 may overcome V561M FGFR1–driven drug resistance in the clinic.

Implications: The V561M FGFR1 gatekeeper mutation leads to devastating drug resistance through activation of STAT3 and the epithelial–mesenchymal transition; this study demonstrates that FGFR1 inhibitor sensitivity can be restored upon STAT3 knockdown.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Received May 4, 2018.
  • Revision received August 6, 2018.
  • Accepted September 17, 2018.
  • Published first September 26, 2018.
  • ©2018 American Association for Cancer Research.
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Molecular Cancer Research: 17 (2)
February 2019
Volume 17, Issue 2
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The FGFR1 V561M Gatekeeper Mutation Drives AZD4547 Resistance through STAT3 Activation and EMT
Molly R. Ryan, Christal D. Sohl, BeiBei Luo and Karen S. Anderson
Mol Cancer Res February 1 2019 (17) (2) 532-543; DOI: 10.1158/1541-7786.MCR-18-0429

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The FGFR1 V561M Gatekeeper Mutation Drives AZD4547 Resistance through STAT3 Activation and EMT
Molly R. Ryan, Christal D. Sohl, BeiBei Luo and Karen S. Anderson
Mol Cancer Res February 1 2019 (17) (2) 532-543; DOI: 10.1158/1541-7786.MCR-18-0429
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Molecular Cancer Research
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