Epithelial–mesenchymal transition confers resistance to selective FGFR inhibitors in SNU-16 gastric cancer cells

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.

Akt Activation Mediates Acquired Resistance to Fibroblast Growth Factor Receptor Inhibitor BGJ398

“…Grygielewicz et al evaluated resistance in SNU-16, a FGFR2 amplified gastric cancer cell line, to FGFR inhibitors AZD4547, BGJ398, and PD173074. While epithelial-mesenchymal transition was primarily implicated as mediating resistance to the FGFR inhibitors, increased levels of pAkt (along with pSTAT and pERK) were observed in the resistant cell lines and treatment with pictilisib, a PI3K inhibitor, was able to restore sensitivity (44). Further, acquired resistance to cetuximab, a monoclonal antibody for EGFR, was associated with Akt activation in lung cancer cell lines and pharmacological inhibition of Akt with the PI3K inhibitor LY294002 enhanced the inhibitory effect of cetuximab (45).…”

Photopreventive Effect and Mechanism of AZD4547 and Curcumin C3 Complex on UVB-Induced Epidermal Hyperplasia

“…The role of FGFR/mTOR signaling should be further validated as a prospective photo-prevention target in skin cancer. Recently, FGF/FGFR signaling has attracted considerable attention for its critical role in endometrial, breast, hepatocellular, gastric, and pancreatic cancer via modulating cell survival, proliferation, and differentiation (30)(31)(32)(33)(34). AZD4547, a pan-FGFR inhibitor, is an exciting novel targeted agent shown to provide efficacy in several phase II clinical trials C3 inhibits UVB and FGF-2-induced mTOR signaling.…”

Discovery of 3-(5′-Substituted)-Benzimidazole-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazoles as Potent Fibroblast Growth Factor Receptor Inhibitors: Design, Synthesis, and Biological Evaluation

“…24 Therefore, it is possible that a common single mutation would confer resistance to these inhibitors, which is classified as a category of genetic alteration contributed to the resistance of FGFR inhibitors besides other categories of compensatory pathway activation and epithelial-to-mesenchymal transition, as revealed by limited studies. 24,[28][29][30] As illustrated in the binding model of 7 in the ATP binding site of FGFR3, 25 Additionally, a hydrogen bond between the pyridyl nitrogen and Asn236 in hydrophobic pocket is observed; this additional hydrogen bond increases FGFR binding affinity. We envisioned that the interaction between the pyridine fragment and the hydrophobic pocket might overcome the resistance of the former three FGFR selective inhibitors (4, 5, and 6) caused by the single mutation as discussed above.…”