A mechanism of resistance to gefitinib mediated by cellular reprogramming and the acquisition of an FGF2-FGFR1 autocrine growth loop

K. E. Ware, T. K. Hinz, E. Kleczko, K. R. Singleton, L. A. Marek, B. A. Helfrich, C. T. Cummings, D. K. Graham, D. Astling, A. C. Tan, L. E. Heasley

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202 Citations (Scopus)


Despite initial and often dramatic responses of epidermal growth factor receptor (EGFR)-addicted lung tumors to the EGFR-specific tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, nearly all develop resistance and relapse. To explore novel mechanisms mediating acquired resistance, we employed non-small-cell lung cancer (NSCLC) cell lines bearing activating mutations in EGFR and rendered them resistant to EGFR-specific TKIs through chronic adaptation in tissue culture. In addition to previously observed resistance mechanisms including EGFR-T790M 'gate-keeper' mutations and MET amplification, a subset of the seven chronically adapted NSCLC cell lines including HCC4006, HCC2279 and H1650 cells exhibited marked induction of fibroblast growth factor (FGF) 2 and FGF receptor 1 (FGFR1) mRNA and protein. Also, adaptation to EGFR-specific TKIs was accompanied by an epithelial to mesenchymal transition (EMT) as assessed by changes in CDH1, VIM, ZEB1 and ZEB2 expression and altered growth properties in Matrigel. In adapted cell lines exhibiting increased FGF2 and FGFR1 expression, measures of growth and signaling, but not EMT, were blocked by FGFR-specific TKIs, an FGF-ligand trap and FGFR1 silencing with RNAi. In parental HCC4006 cells, cell growth was strongly inhibited by gefitinib, although drug-resistant clones progress within 10 days. Combined treatment with gefitinib and AZD4547, an FGFR-specific TKI, prevented the outgrowth of drug-resistant clones. Thus, induction of FGF2 and FGFR1 following chronic adaptation to EGFR-specific TKIs provides a novel autocrine receptor tyrosine kinase-driven bypass pathway in a subset of lung cancer cell lines that are initially sensitive to EGFR-specific TKIs. The findings support FGFR-specific TKIs as potentially valuable additions to existing targeted therapeutic strategies with EGFR-specific TKIs to prevent or delay acquired resistance in EGFR-driven NSCLC.

Original languageEnglish
Article numbere39
Publication statusPublished - 2013

Bibliographical note

Funding Information:
This research was supported by NIH grants P50 CA58187 and R01 CA127105. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. DNA sequencing and cell line fingerprinting were performed through the University of Colorado Cancer Center Molecular Pathology shared resource facility. The completion of the deep sequencing for the RNA-seq analysis was performed by the University of Colorado Next-Generation Sequencing Development Core. Investigational drugs were provided through materials transfer agreements with AstraZeneca and Five Prime Therapeutics.


  • EGFR
  • FGF2
  • FGFR1
  • acquired resistance
  • gefitinib

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research


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