Altered Splicing of FGFR1 Is Associated with High Tumor Grade and Stage and Leads to Increased Sensitivity to FGF1 in Bladder Cancer

Abstract

Fibroblast growth factor receptors (FGFRs) play key roles in proliferation, differentiation, and tumorigenesis. Previously, we demonstrated that FGFR1 expression is increased in urothelial carcinoma cell lines and tumors, which promotes proliferation and survival via activation of the mitogen-activated protein kinase (MAPK) pathway. Here we examined splice variants of FGFR1 in both urothelial carcinoma cell lines and tumors. Two known FGFR1 IIIc splice variants (FGFR1␣ and FGFR1␤) were expressed. FGFR1␤ lacks exon 3 of FGFR1␣, removing the first Ig loop of the extracellular domain. Both isoforms were expressed at similar levels in normal urothelial cells, but FGFR1␤ was expressed at higher levels in most tumor cell lines. In tumor tissues, expression levels were higher than in controls, and the FGFR1␤: FGFR1␣ ratio was significantly increased in association with tumor stage and grade. When FGFR1␣ and FGFR1␤ were expressed in urothelial cells, no differences in signaling were observed. FGFR1-induced proliferation paralleled MAPK pathway activation. The relative activation of FGFR1␤ and FGFR1␣ by all known mammalian FGFs was examined. Both isoforms were activated by the same FGFs, but the level of activation differed. FGFR1␤ showed higher affinity for low concentrations of FGF1, leading to enhanced signaling and increased proliferation. An FGFR1␣-to-FGFR1␤ isoform switch and increased FGF1-induced activation of FGFR1␤ may result in a proliferative advantage that plays a key role during bladder tumor progression.

Advanced urothelial carcinoma: next-generation sequencing reveals diverse genomic alterations and targets of therapy

“…42 As a protein assayed by IHC, FGFR1 is frequently overexpressed in urothelial carcinoma, and has been associated with MAPK pathway activation and the epithelial-mesenchymal transition. [43][44][45] Three UCs in this series featured FGFR1 amplifications, consistent with FGFR1 being commonly amplified in human cancers, and has been previously reported in approximately 3% of UCs. 39,45 FGFR mRNA overexpression has also been reported in UC.…”

“…39,45 FGFR mRNA overexpression has also been reported in UC. 43 An FDA-approved therapy for another indication, ponatinib, does inhibit FGFR1 and may be useful in the setting of FGFR1 amplification. Clinical trials of this and other FGFR inhibitors are also currently underway.…”

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of Transformation by Amplified FGFR1 in Lung Cancer

“…The FGFR family consists of four receptor tyrosine kinases, which are common targets of deregulation by translocation, point mutation, and amplifi cation in cancer (12)(13)(14). FGFRs are activated via 22 different FGF ligands resulting in downstream FRS2 and extracellular signal-regulated kinase (ERK) phosphorylation ( 13 ); their signaling is modulated endogenously by multiple negative intrinsic feedback loops (15)(16)(17).…”

Fibroblast Growth Factor Receptor 1 as a Target for the Therapy of Renal Cell Carcinoma

“…This can affect the ligand binding strength and the activity of therapeutic agents directed against the receptor [6,7]. Furthermore, data are available on the different proliferative activities of tumor cells when FGF binds to different subunits of domain IIIc: 1α or 1β [8]. …”