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

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.

Genetic modifiers of EGFR dependence in non-small cell lung cancer

“…Similarly, we noted that fibroblast growth factor receptor (FGFR) family kinase genes FGFR1 and FGFR2, though not previously recognized as sufficient for EGFR bypass, nonetheless align with previous work describing up-regulation of FGFR1 as well as the ligand FGF2 in gefitinib-resistant NSCLC models, with concomitant dependency on the FGFR pathway (33,34), and with other studies implicating FGF ligands in TKI resistance (15,35).…”

FGFR1 Is a Potential Prognostic Biomarker and Therapeutic Target in Head and Neck Squamous Cell Carcinoma

“…Thus, FGFR1 is a potential therapeutic target in HNSCC and AZD4547/gefitinib combination therapy could be adopted to overcome EGFR mediated therapy resistance. The role of EGFR signalling as a resistance mechanism to FGFR inhibitor treatment has previously been reported in several tumor types, including HNSCC (19,36). Furthermore, combining radiotherapy with AZD4547 may be of interest for treating HNSCC, as previous studies report an increased sensitivity of prostate cancer and mesothelioma to radiotherapy when combined with FGFR1 inhibitors (37,38).…”

Long Pentraxin-3 Inhibits Epithelial–Mesenchymal Transition in Melanoma Cells

“…Also, we provide novel insights about the role of the FGF2/FGFR1 system in melanoma progression by showing that PTX3 overexpression inhibits EMT in these cells. The FGF/FGFR system has been shown to modulate EMT in breast (37), cervical (38), colon (39), bladder (40), and prostate (41) cancer. To the best of our knowledge, our data provide the first experimental evidence about a nonredundant role of the FGF/FGFR system in the modulation of the EMT process in melanoma.…”