Discovery of Resistance Pathways to Fibroblast Growth Factor Receptor inhibition in Bladder Cancer
BackgroundAberrant fibroblast growth factor receptor (FGFR) signaling drives the growth of many bladder cancers. NVP-BGJ398 is a small molecule with potent inhibitory activity of FGFRs 1, 2, and 3, and has been shown to selectively inhibit the growth of bladder cancer cell lines that over-express FGFR3 or have oncogenic FGFR3 fusions. As with many agents targeting receptor tyrosine kinases, resistance is known to develop.\n\nObjectiveWe sought to identify potential mechanisms of resistance to NVP-BGJ398 in cell culture models of bladder cancer.\n\nMethodsRT-112 bladder cancer cell lines were derived that were resistant to growth in 3uM NVP-BGJ398. RNA-sequencing was performed on resistant and parental cell lines to identify potential resistance mechanisms and molecular experiments were carried out to test these predictions.\n\nResultsRNA-seq demonstrated decreased expression of FGFR3 and increased expression of FGFRs 1 and 2 in resistant cell lines. Over-expression of FGFR3 in NVP-BGJ398 resistant cells decreased their proliferation. Pathway analysis of RNA-seq data also implicated PIM kinase signaling, among other pathways, as a potential mediator of resistance. Treatment of BGJ398 resistant cells with the PIM kinase inhibitor SGI-1776 reduced the growth of the cells.\n\nConclusionsOur results suggest that altered FGFR expression and PIM kinase activity could mediate resistance to NVP-BGJ398. These pathways should be investigated in samples from patients resistant to this drug.