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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
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The FGFR1 V561M Gatekeeper Mutation Drives AZD4547 Resistance through STAT3 Activation and EMT

Molly R Ryan1, Christal D Sohl1, BeiBei Luo1

  • 1Department of Pharmacology, Yale University, New Haven, Connecticut.

Molecular Cancer Research : MCR
|September 28, 2018
PubMed

Insights

Drug resistance in FGFR1-mutated lung cancer is driven by the V561M mutation, which activates STAT3. Restoring sensitivity to FGFR1 inhibitors like AZD4547 can be achieved by targeting STAT3.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Fibroblast Growth Factor Receptor 1 (FGFR1) is implicated in various cancers, including squamous cell lung cancer.
  • Targeted therapies like AZD4547 show promise but face challenges due to drug resistance.
  • The V561M gatekeeper mutation in FGFR1 is a known mechanism of resistance, but its precise role in AZD4547 resistance is not fully understood.

Purpose of the Study:

  • To investigate the cellular consequences of the V561M gatekeeper mutation in FGFR1.
  • To elucidate the mechanisms by which V561M confers resistance to the FGFR1 inhibitor AZD4547.
  • To identify potential therapeutic strategies to overcome V561M-mediated drug resistance.

Main Methods:

  • In vitro binding assays to assess AZD4547 affinity for V561M FGFR1.
  • Cellular assays to evaluate proliferation, migration, invasion, and anchorage-independent growth.
  • Cytometry by Time-Of-Flight (CyTOF) for single-cell analysis.
  • Short hairpin RNA (shRNA) mediated knockdown of STAT3.

Main Results:

  • Despite maintaining nanomolar affinity for V561M FGFR1, AZD4547 treatment resulted in dramatic resistance in cells expressing this mutation.
  • V561M FGFR1 activation led to increased STAT3 activation, promoting a mesenchymal phenotype with enhanced proliferation, migration, and invasion.
  • Knockdown of STAT3 restored sensitivity of V561M FGFR1-expressing cancer cells to AZD4547.

Conclusions:

  • The V561M gatekeeper mutation confers resistance to AZD4547 by activating STAT3 and promoting epithelial-mesenchymal transition.
  • Combination therapies targeting both FGFR1 and STAT3 may be a viable strategy to overcome V561M-driven drug resistance in clinical settings.
  • STAT3 inhibition presents a promising approach to restore sensitivity to FGFR1 inhibitors in resistant cancers.

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