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Which FGFR isoform drives cancer?

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The promise of FGFR inhibitors in the clinic, but which FGFR isoform drives cancer?

Urothelial cancer (UC) is the fifth most common malignancy of the genitourinary system in Canada (1) and its treatment has proven to be challenging. At the molecular level, overexpression as a result of genetic alterations of the Fibroblast Growth Factor Receptor (FGFR) kinase, a family of 4 different proteins, underlies UC. Inhibition of the FGFR signalling is key to successfully treating UC and this has already been achieved by small molecule-based drugs that have been tested in the clinic (2). One such drug that is currently seeking approval by the FDA is Erdafitinib (ERDA; JNJ-42756493), a once-daily oral pan-FGFR inhibitor that awaits its approval for the treatment of metastatic UC, where patients have limited treatment options.

Erdafitinib binds to and blocks activity of all 4 FGFR proteins. However the question remains as to which specific isoforms of this receptor tyrosine kinase family is the driver of cancer. FGFR1 – 4 comprise a family of highly conserved receptors involved in a multitude of biological processes including cell growth, differentiation, angiogenesis, wound healing and tumourigenesis. As a result of alternative splicing, several FGFR isoforms are formed including b and c variants in FGFR 1 -3, having a large impact on ligand-binding of the affected FGFRs. Dysregulated FGFR signalling is associated with human disease; in particular, it is upregulated in many tumour cell types (3). Understanding the driver FGFR isoform would benefit the development of more tailored inhibitors with more promising clinical outcomes.

In collaboration with the University of Toronto, CCAB has identified specific antibodies that explicitly discern 6 isoforms: FGFR1c (MM-0307), FGFR2b (MM-0308), FGFR2c (MM-0309), FGFR3b (MM-0310), FGFR3c (MM-0311), FGFR4 (MM-0312). Sold both individually and as a convenient profiler panel (MM-0313) by MediMabs, CCAB’s distributor of its reagent antibodies, researchers can use these unique products to profile any of the 6 different isoforms in their favoured cell systems. The novelty of offering an FGFR Antibody Profiler Set in the reagent market will give researchers the advantage of understanding FGFR isoforms at the molecular level. With such powerful tools now available in the market, a new path is possible to design and develop more targeted therapeutic approaches to specifically inhibit FGFR isoforms leading to more effective treatments in the future.