• What is FGFR3?
  • FGFR3 in Bladder Cancer
  • Clinical Trials

FGFR3

The fibroblast growth factor receptor 3 (FGFR3) gene (Figure 1) encodes one member of the FGF receptor tyrosine kinase family, which includes four kinases: FGFR1, FGFR2, FGFR3, and FGFR4. FGFR tyrosine kinases belong to the immunoglobulin superfamily and act as receptors for the various fibroblast growth factors (FGFs). FGFR3 consists of three extracellular immunoglobulin-like domains, a transmembrane domain, and an intracellular split kinase domain with two contiguous active regions (Ahmad, Iwata, and Leung 2012; Dienstmann et al. 2014; Goetz and Mohammadi 2013; Kelleher et al. 2013; di Martino, Tomlinson, and Knowles 2012; Touat et al. 2015). Canonical models of FGF-FGFR signaling hold that binding of FGF ligands, in coordination with heparin sulphate, to the extracellular domains promotes receptor dimerization and autophosphorylation of the tyrosine kinase domains, thereby activating these enzymes (Adar et al. 2002; d'Avis et al. 1998; Goetz and Mohammadi 2013; Kelleher et al. 2013; Schlessinger et al. 2000; Tomlinson et al. 2007; Touat et al. 2015; Turner and Grose 2010). However, recent biophysical evidence suggests that full length FGFRs, in particular FGFR3, can dimerize in the absence of ligand at physiological concentrations and that FGFR3 responds with different levels of activation to different FGF ligands (Sarabipour and Hristova 2016).

After activation, FGFRs are involved in downstream signaling via the MAP kinase, JAK/STAT, and PI3K/AKT pathways (Figure 2). They play crucial roles in development, differentiation, cell survival, and cell migration (Ahmad, Iwata, and Leung 2012; Dienstmann et al. 2014; Kelleher et al. 2013). FGFR3 has been shown in cancers to be dysregulated by amplification, missense mutation, fusion, or translocation, with most carcinogenic mutations having an activating effect on FGFR3 (di Martino, Tomlinson, and Knowles 2012). FGFR3 gene aberrations have been reported in urothelial, breast, head and neck, lung, brain, gastric, pancreatic, colorectal, kidney, endometrial, ovarian, and cervical cancers (Dienstmann et al. 2014; Helsten et al. 2016; Kelleher et al. 2013; Parker et al. 2014; Touat et al. 2015) and are known to be highly prevalent in bladder cancers (di Martino, Tomlinson, and Knowles 2012).

Many oncogenic FGFR3 missense mutations are activating, potentially through mechanisms that promote constitutive dimerization of FGFR3 or by conformational activation of the TK domain (Lievans, Roncador, and Liboi 2006; di Martino, Tomlinson, and Knowles 2012; Tomlinson et al. 2007; Touat et al. 2015; Webster et al. 1996). However, more recent biophysical work demonstrates that cysteine mutations in the extracellular and transmembrane domains, formerly thought to act by promoting constitutive dimerization, only result in modest dimer stabilization in absence of ligand and instead lead to structural changes of the dimers (Piccolo, Placone, and Hristova 2014). FGFR3 fusions have also been implicated in dimerization, as they introduce dimerization domains that may promote constitutive dimerization (Parker et al. 2014). FGFR3 amplification and FGFR3 overexpression may result in enhanced ligand-free dimerization and signaling due to locally enhanced FGFR3 concentrations in the membrane and/or enhanced signaling due to concomitant FGF ligand overexpression (di Martino, Tomlinson, and Knowles 2012; Sarabipour and Hristova 2016). Recent work suggests that FGFR3 adopts several active dimer conformations and that activating mutations may act by locking FGFR3 into the most active of these conformations even in the absence of ligand (Sarabipour and Hristova 2016).

FGFR3 gene

Figure 1. Diagram of the FGFR3 protein domains and corresponding FGFR3 coding exons. SP = signal peptide; Ig = immunoglobulin-like domain; AB = acid box; TM = transmembrane domain; TK = tyrosine kinase domain. For comprehensive information of the FGFR3 gene and FGFR3 protein, see reviews in Ahmad, Iwata, and Leung 2012; Dienstmann et al. 2014; Goetz and Mohammadi 2013; di Martino, Tomlinson, and Knowles 2012; Touat et al. 2015;Turner and Grose 2010.

FGFR3 signaling

Figure 2. Fibroblast growth factor receptors (FGFRs) consist of extracellular Ig-like domains, a transmembrane domain, and a bipartite tyrosine kinase (TK) domain. The Ig I domain is postulated to be involved in auto-inhibition, while the Ig II and Ig III domains are involved in fibroblast growth factor (FGF) ligand binding. Multiple isoforms of the receptor are generated by alternative splicing, which affects the Ig III domain. Canonical models state that FGF binding to the FGFR induces receptor dimerization and trans-phosphorylation of the TK domain, thereby activating the kinase function. The activated kinase binds to a number of adaptor proteins and also phosphorylates downstream substrates, thereby inducing signaling via a number of pathways, including the MAP kinase pathway, the JAK/STAT pathway, and the PI3K/AKT pathway. These pathways alter a number of cellular processes that can lead to alterations in gene transcription, metabolic regulation, and cell growth, survival, proliferation, and differentiation. TK inhibitors that act on FGFR3 bind to the intracellular TK domain, while therapeutic antibodies targeting FGFR3 act on the extracellular domains. For comprehensive information of the FGFR activated pathways and FGFR signaling in cancer, see reviews in Ahmad, Iwata, and Leung 2012; Dienstmann et al. 2014; Goetz and Mohammadi 2013; Kelleher et al. 2013; di Martino, Tomlinson, and Knowles 2012; Touat et al. 2015;Turner and Grose 2010.

Related Pathways

Contributors: Christine M. Lovly, M.D., Ph.D., Peter Hammerman, M.D., Ph.D.

Suggested Citation: Lovly, C., P. Hammerman. 2016. FGFR3. My Cancer Genome https://www.padiracinnovation.org/content/disease/bladder-cancer/fgfr3/?tab=0 (Updated January 28).

Last Updated: January 28, 2016

FGFR3 in Bladder Cancer

FGFR3 mutations are found in about 50% of upper and lower urinary tract tumors (di Martino, Tomlinson, and Knowles 2012). These mutations cluster in exons 7 and 10, which encode portions of the extracellular domain and the entirety of the transmembrane domain, and exon 15, which encodes a portion of the tyrosine kinase domain (Billerey et al. 2001; Burger et al. 2008; Hernandez et al. 2006; di Martino, Tomlinson, and Knowles 2012; Tomlinson et al. 2007a; van Oers et al. 2009; van Rhijn et al. 2002). The most common mutations are found in exons 7 and 10 and introduce non-native cysteine or glutamate residues, allowing the formation of intermolecular disulfide bonds or hydrogen bonds; these disulfide bonds may induce ligand-free dimerization and constitutive activation of FGFR3 (Adar et al. 2002; d'Avis et al. 1998; di Martino, Tomlinson, and Knowles 2012; Tomlinson et al. 2007a; Touat et al. 2015). However, more recent biophysical work demonstrates that cysteine mutations in the extracellular and transmembrane domains, formerly thought to act by promoting constitutive dimerization, only result in modest dimer stabilization in absence of ligand and instead lead to structural changes of the dimers (Piccolo, Placone, and Hristova 2014). The most prevalent of these mutations encodes the amino acid change S249C, which accounts for ~61% of all FGFR3 mutations in bladder cancers. The other commonly found exon 7 and 10 mutations include those encoding the amino acid changes Y375C (~19%), R248C (~8%), and G372C (~6%) (di Martino, Tomlinson, and Knowles 2012). Mutations in exon 15 (encoding K652E, K652Q, K652T, or K652M) account for only about 2% of FGFR3 mutations in bladder cancer (di Martino, Tomlinson, and Knowles 2012). Exon 15 mutations are thought to act by altering the conformation of the kinase domain into a constitutively active state or by inducing aberrant FGFR3 cellular localization (Lievans, Roncador, and Liboi 2006; di Martino, Tomlinson, and Knowles 2012; Webster et al. 1996). FGFR3 fusions have also been described in association with bladder cancer, including an FGFR3–transforming acid coiled-coil 3 (TACC3) fusion and an FGFR–BAI1-associated protein 2-like 1 (BAIAP2L1) fusion (Williams et al. 2013). The FGFR3-BAIAP2L1 fusion protein appears to promote constitutive activation via dimerization (Nakanishi et al. 2015). Mutated FGFR3 also correlates with increased FGFR3 protein expression, although up to 40% of wild-type tumors also display FGFR3 overexpression (di Martino, Tomlinson, and Knowles 2012). In a large-scale analysis by next generation sequencing, FGFR3 amplification was found in around 2% of urothelial carcinomas (Helsten et al. 2016). Combined, FGFR3-signaling dysregulation by mutation or overexpression is found in 81% of non-invasive and 54% of invasive urothelial cancers (Tomlinson et al. 2007a). Additionally, in vitro evidence suggests that splice variant switching to an isoform with a broader ligand profile (specifically from FGFR3b to the FGFR3c isoform) may play a role in enhanced signaling through the FGFR3 pathway in bladder cancers (Tomlinson et al. 2005).

Because of the high frequency of FGFR3 mutations in bladder cancer, FGFR3 mutations are currently being investigated as a diagnostic biomarker for non-invasive cancer diagnosis and monitoring via urine collection and next-generation sequencing applications (Kandimalla et al. 2013; Millholland et al. 2012; Noel et al. 2015). Case report evidence indicates that detecting FGFR3 mutations in voided urine is useful in the diagnostic clinical setting (Silverberg 2012). Further, clinical evidence demonstrates that urinary FGFR3 mutation analysis is useful in predicting recurrence in patients with an FGFR3-mutated primary tumor and may be able to partially replace cystoscopy in the clinical setting (Couffignal et al. 2015; van Kessel et al. 2013).

Ultimately, FGFR3 is an attractive therapeutic target in bladder cancer given the high frequency of FGFR3 aberrations observed in this patient cohort, but clinical evidence of effective therapeutic agents targeting FGFR3 is still limited. Preliminary phase I clinical trial data indicate that the novel pan-FGFR inhibitor BGJ398 induces tumor regression in bladder cancers with FGFR3-activating mutations (Sequist et al. 2014). The pan-FGFR inhibitor JNJ-42756493 demonstrated partial response in a single patient with bladder cancer harboring a FGFR3-TACC3 fusion (Bahleda et al. 2014). Other preclinical reports suggest that FGFR3 fusion proteins are highly sensitive to FGFR-selective agents in in vitro and in vivo settings (Williams et al. 2013; Wu et al. 2013). In contrast, another tyrosine kinase inhibitor, dovitinib, showed such limited single-agent activity in both FGFR3-mutated and FGFR3-WT urothelial carcinomas that a clinical trial of this drug was halted prematurely (Milowsky et al. 2014). Additional preclinical data indicate that FGFR3-mutated bladder cancer xenografts are responsive to targeted FGFR3 antibody therapy with the antibody R3Mab (Gust et al. 2013). Finally, preclinical reports suggest that combination FGFR and EGFR therapies may be important in mediating resistance to FGFR-targeting in FGFR3-mutated cancers (Herrera-Abreu et al. 2013).

Last Updated: February 13, 2017

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