Abstract
BackgroundUp to 10 % of primary gastric cancers are characterized by FGFR2 amplification, and fibroblast growth factor receptor (FGFR) inhibitors may represent therapeutic agents for patients with these malignancies. However, long-term benefits of the treatment might be limited owing to the occurrence of drug resistance.MethodsTo investigate the mechanisms of resistance to selective FGFR inhibitors, we established three FGFR2-amplified SNU-16 gastric cancer cell lines resistant to AZD4547, BGJ398, and PD173074, respectively.ResultsThe resistant cell lines (SNU-16R) demonstrated changes characteristic of epithelial-to-mesenchymal transition (EMT). In addition, they displayed loss of expression of FGFR2 and other tyrosine kinase receptors concurrent with activation of downstream signaling proteins and upregulation of the transforming growth factor β (TGF-β) level. However, treatment of parental SNU-16 cells with TGF-β1 did not evoke EMT, and pharmacological inhibition of TGF-β receptor I was not sufficient to reverse EMT changes in the resistant cells. Finally, we showed that the SNU-16R cell lines were sensitive to the human epidermal growth factor receptor 2 inhibitor mubritinib and the heat shock protein 90 inhibitor AUY922.ConclusionIn conclusion, we provide experimental evidence that EMT-mediated resistance might emerge in gastric cancer patients following treatment with FGFR inhibitors, and mubritinib or AUY922 treatment may be an alternative therapeutic strategy for these patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s10120-014-0444-1) contains supplementary material, which is available to authorized users.
Highlights
The fibroblast growth factor (FGF) receptors (FGFRs) constitute one of the most extensively studied novel therapeutic targets in the field of anticancer drug development
To generate SNU-16 gastric cancer cell lines resistant to AZD4547 (AZDR), BGJ398 (BGJR), and PD173074 (PDR), SNU-16 cells were cultured with increasing concentrations of the respective fibroblast growth factor receptor (FGFR) inhibitor
Consistent with the ability of resistant cells to grow at high concentrations of a particular FGFR inhibitor, AZDR, BGJR, and PDR cells were highly resistant to AZD4547, BGJ398, or PD173074, respectively, with an IC50 of approximately 10 lM (Fig. 1)
Summary
The fibroblast growth factor (FGF) receptors (FGFRs) constitute one of the most extensively studied novel therapeutic targets in the field of anticancer drug development. Since aberrantly activated FGFR kinases serve as an oncogenic ‘‘driver,’’ a great number of FGFR inhibitors are currently in clinical development. No selective small-molecule FGFR inhibitor has been approved for clinical use. The first selective FGFR inhibitor developed was PD173074, which, despite its high selectivity and cellular activity, has never entered clinical use [10]. Only a few selective FGFR inhibitors are under clinical investigation, and the two in the most advanced stage are AZD4547 and BGJ398, developed by AstraZeneca and Novartis, respectively [11, 12]. Up to 10 % of primary gastric cancers are characterized by FGFR2 amplification, and fibroblast growth factor receptor (FGFR) inhibitors may represent therapeutic agents for patients with these malignancies. Long-term benefits of the treatment might be limited owing to the occurrence of drug resistance
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