Targeting mutant fibroblast growth factor receptors in cancer

Abstract

Fibroblast growth factor receptors (FGFRs) play diverse roles in the control of cell proliferation, cell differentiation, angiogenesis and development. Activating the mutations of FGFRs in the germline has long been known to cause a variety of skeletal developmental disorders, but it is only recently that a similar spectrum of somatic FGFR mutations has been associated with human cancers. Many of these somatic mutations are gain-of-function and oncogenic and create dependencies in tumor cell lines harboring such mutations. A combination of knockdown studies and pharmaceutical inhibition in preclinical models has further substantiated genomically altered FGFR as a therapeutic target in cancer, and the oncology community is responding with clinical trials evaluating multikinase inhibitors with anti-FGFR activity and a new generation of specific pan-FGFR inhibitors.

Figure 2

Alignment of altered amino acids encoded by somatic mutations found in FGFRs that are known or likely to be oncogenic (Table 1). Unique amino acid substitutions are represented by green circles. Amino acid numbers are derived from the following reference transcripts: FGFR1, NM_000604; FGFR2, NM_022970; FGFR3, NM_000142; FGFR4, NM_002011. Yellow, Ig-like domains; red, kinase domains.

Figure 1

Schematic diagram of signal transduction pathway activated by ligand-stimulated FGFRs. Ligand specificity is determined in part by an alternative splicing event in the C-terminal half of the third immunoglobulin domain (bright blue) in which either exon 8 or exon 9 can be used, producing the IIIb and IIIc isoforms, respectively. Ligand binding results in receptor autophosphorylation in the kinase domain region and phosphorylation of FRS2, which initiates a signaling cascade resulting in activation of the AKT and ERK downstream signaling pathways.