Small molecule FGF receptor inhibitors block FGFR-dependent urothelial carcinoma growth in vitro and in vivo

Abstract

Background:Activating mutations of FGFR3 are frequently identified in superficial urothelial carcinoma (UC) and increased expression of FGFR1 and FGFR3 are common in both superficial and invasive UC.Methods:The effects of inhibition of receptor activity by three small molecule inhibitors (PD173074, TKI-258 and SU5402) were investigated in a panel of bladder tumour cell lines with known FGFR expression levels and FGFR3 mutation status.Results:All inhibitors prevented activation of FGFR3, and inhibited downstream MAPK pathway signalling. Response was related to FGFR3 and/or FGFR1 expression levels. Cell lines with the highest levels of FGFR expression showed the greatest response and little or no effect was measured in normal human urothelial cells or in UC cell lines with activating RAS gene mutations. In sensitive cell lines, the drugs induced cell cycle arrest and/or apoptosis. IC50 values for PD173074 and TKI-258 were in the nanomolar concentration range compared with micromolar concentrations for SU5402. PD173074 showed the greatest effects in vitro and in vivo significantly delayed the growth of subcutaneous bladder tumour xenografts.Conclusion:These results indicate that inhibition of FGFR1 and wild-type or mutant FGFR3 may represent a useful therapeutic approach in patients with both non-muscle invasive and muscle invasive UC.

E7090, a Novel Selective Inhibitor of Fibroblast Growth Factor Receptors, Displays Potent Antitumor Activity and Prolongs Survival in Preclinical Models

“…36). Consistent with our results, J82, a human bladder cancer cell line harboring an FGFR3 K652E mutation, has been reported to be insensitive to FGFR inhibitors due to low protein expression (37). Another reason may be activation of other signaling pathways, which reduce activity of the FGFR inhibitor.…”

Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives

“…Actions intended to target FGFR3 reduced cell proliferation and tumor growth in both bladder cancer cells and mouse models ( 43 ). In human bladder cancer, FGFR3 mutations are strongly related to low-grade, nonmuscle-invasive tumors and good prognosis ( 44 ).…”

Targeting multiple tyrosine kinase receptors with Dovitinib blocks invasion and the interaction between tumor cells and cancer-associated fibroblasts in breast cancer

“…9 Among these cytokines, CCL2 and CCL5, which are known inflammatory mediators, were demonstrated to play important role in the mediation of the interaction between CAFs and breast cancer cells beyond SDF-1 [10][11][12][13] Dovitinib (formerly CHIR-258, TKI-258, Novartis pharmaceuticals) is an investigational new inhibitor of multiple tyrosine kinases that has in vitro inhibitory activity against basic fibroblast growth factor receptor (bFGFR), platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptor (VEGFR) kinases with IC 50 values of approximately 10 nM. Further in vivo and in vitro data indicate that this drug blocked PDGFR/FGFR/VEGFR signaling in advanced melanoma, 4 pancreatic cancer, 14 breast carcinoma, 15 urothelial carcinoma, 16 impaired tumor growth, angiogenesis, and metastasis by effects on tumor cells, endothelial cells, and pericytes in vitro. 14,15 Due to the important role of PDGFs and FGFs in the supportive effect of CAFs for the breast tumor progression through the autocrine or paracrine fashion, [17][18][19] we hypothesized that targeting PDGFR and FGFR signaling by Dovitinib could block the cross-talk of CAFs-tumor cell and inhibit cell invasion of breast cancer.…”