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, Aik-Choon Tan, L. E. Heasley

Research output: Contribution to journalArticle

150 Citations (Scopus)

Abstract

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
JournalOncogenesis
Volume2
DOIs
Publication statusPublished - 2013 Jul 29
Externally publishedYes

Fingerprint

Fibroblast Growth Factor 1
Fibroblast Growth Factor Receptors
Fibroblast Growth Factor 2
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Growth
Non-Small Cell Lung Carcinoma
Cell Line
Epithelial-Mesenchymal Transition
Clone Cells
Receptor, Fibroblast Growth Factor, Type 1
Cellular Reprogramming
gefitinib
Mutation
Fibroblast Growth Factors
Receptor Protein-Tyrosine Kinases
RNA Interference
Pharmaceutical Preparations
Lung Neoplasms
Ligands

Keywords

  • acquired resistance
  • EGFR
  • FGF2
  • FGFR1
  • gefitinib
  • NSCLC

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology

Cite this

Ware, K. E., Hinz, T. K., Kleczko, E., Singleton, K. R., Marek, L. A., Helfrich, B. A., ... Heasley, L. E. (2013). A mechanism of resistance to gefitinib mediated by cellular reprogramming and the acquisition of an FGF2-FGFR1 autocrine growth loop. Oncogenesis, 2, [e39]. https://doi.org/10.1038/oncsis.2013.4

A mechanism of resistance to gefitinib mediated by cellular reprogramming and the acquisition of an FGF2-FGFR1 autocrine growth loop. / Ware, K. E.; Hinz, T. K.; Kleczko, E.; Singleton, K. R.; Marek, L. A.; Helfrich, B. A.; Cummings, C. T.; Graham, D. K.; Astling, D.; Tan, Aik-Choon; Heasley, L. E.

In: Oncogenesis, Vol. 2, e39, 29.07.2013.

Research output: Contribution to journalArticle

Ware, KE, Hinz, TK, Kleczko, E, Singleton, KR, Marek, LA, Helfrich, BA, Cummings, CT, Graham, DK, Astling, D, Tan, A-C & Heasley, LE 2013, 'A mechanism of resistance to gefitinib mediated by cellular reprogramming and the acquisition of an FGF2-FGFR1 autocrine growth loop', Oncogenesis, vol. 2, e39. https://doi.org/10.1038/oncsis.2013.4
Ware, K. E. ; Hinz, T. K. ; Kleczko, E. ; Singleton, K. R. ; Marek, L. A. ; Helfrich, B. A. ; Cummings, C. T. ; Graham, D. K. ; Astling, D. ; Tan, Aik-Choon ; Heasley, L. E. / A mechanism of resistance to gefitinib mediated by cellular reprogramming and the acquisition of an FGF2-FGFR1 autocrine growth loop. In: Oncogenesis. 2013 ; Vol. 2.
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