ASP5878, a selective FGFR inhibitor, to treat FGFR3‐dependent urothelial cancer with or without chemoresistance

Abstract

FGF/FGFR gene aberrations such as amplification, mutation and fusion are associated with many types of human cancers including urothelial cancer. FGFR kinase inhibitors are expected to be a targeted therapy for urothelial cancer harboring FGFR3 gene alternations. ASP5878, a selective inhibitor of FGFR1, 2, 3 and 4 under clinical investigation, selectively inhibited cell proliferation of urothelial cancer cell lines harboring FGFR3 point mutation or fusion (UM‐UC‐14, RT‐112, RT4 and SW 780) among 23 urothelial cancer cell lines. Furthermore, ASP5878 inhibited cell proliferation of adriamycin‐resistant UM‐UC‐14 cell line harboring MDR1 overexpression and gemcitabine‐resistant RT‐112 cell line. The protein expression of c‐MYC, an oncoprotein, in gemcitabine‐resistant RT‐112 cell line was higher than that in RT‐112 parental cell line and ASP5878 decreased the c‐MYC expression in both RT‐112 parental and gemcitabine‐resistant RT‐112 cell lines. Once‐daily oral administration of ASP5878 exerted potent antitumor activities in UM‐UC‐14, RT‐112 and gemcitabine‐resistant RT‐112 xenograft models without affecting body weight. These findings suggest that ASP5878 has the potential to be an oral targeted therapy against urothelial cancer harboring FGFR3 fusion or FGFR3 point mutation after the acquisition of gemcitabine‐ or adriamycin‐resistance.

Identification of a novel oncogenic mutation of FGFR4 in gastric cancer

“…4A(b)). This effect on growth was comparable to those of other ASP5878-sensitive cell lines, which are dependent on FGFR4 signalling 25,26 .

Figure 4Antiproliferative effect of an FGFR inhibitor and 3D structures of FGFR4. ( A ) Antiproliferative effect of ASP5878 on (a) G636C-FGFR4/BaF3 and (b) G636C-FGFR4/3T3 cells.

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“…Our results predict the activation of an oncogenic signaling pathway by FGFR4-G636C . To support this prediction, we treated G636C-R4/BaF3 and G636C-R4/3T3 cells with the selective FGFR inhibitor ASP5878 25,26 . G636C-R4/BaF3 cells were sensitive to ASP5878 (IC 50 , 34.4 nmol/L [95% CI: 24.6–48.2]) in the absence of IL-3 (Fig.…”

Ramucirumab and Docetaxel in Patients with Metastatic Urothelial Carcinoma Harboring Fibroblast Growth Factor Receptor Alterations: A Case Series and Literature Review

“…In UC, several alterations in FGFR have been reported, indicating that FGFR inhibitors are a potential approach to individualize therapy. [10][11][12][13][14][15] In this case series, we reported two patients with mUTUC that carried an FGFR alteration and progressed after receiving FGFR inhibitor treatment that later showed clinical benefit to ramucirumab and docetaxel.…”

“…For reprints contact: reprints@medknow.com with FGFR3 mutations found in 21% of patients. [10][11][12][13][14][15] Another recent finding involves ramucirumab, an anti-vascular endothelial growth factor (VEGF) antibody, which is associated with improved progression-free survival (PFS) and objective responses when used with docetaxel. [16][17][18] However, there are no studies evaluating the efficacy of ramucirumab and docetaxel in relation to genetic alterations and how to best sequence different therapies.…”

FGFR Signaling Coordinates the Balance Between Glycolysis and Fatty Acid β-Oxidation in Lymphatic Endothelial Cells

“…Cellular energy in LECs is produced by glycolysis, glucose oxidation, glutamine oxidation, and FAO [21,16]. To assess the potential impact of FGFR signaling on the other metabolic processes that generate energy, we treated proliferating human dermal LECs (HDLECs) with 200 nM ASP5878, a highly specific FGFR inhibitor [25,26], for 2 days. HDLECs were cultured in EC growth medium and kept at subconfluency throughout the experiments to be maintained in the proliferative state.…”