The fibroblast growth factor receptor type 1 gene (FGFR1) encodes one member of the FGFR tyrosine kinase (TK) family, which includes four kinases: FGFR1, 2, 3, and 4 (Figure 1). FGFR TKs play crucial roles in development and have been shown in cancers to be deregulated by either amplification, point mutation, or translocation (Turner and Grose 2010). Amplification or activation of FGFR1 has been reported in many cancers including oral squamous cell carcinoma (Freier et al. 2007), breast cancer (Turner et al. 2010), esophageal squamous cell carcinoma (Ishizuka et al. 2002), ovarian cancer (Gorringe et al. 2007), bladder cancer (Simon et al. 2001), prostate cancer (Edwards et al. 2003), and lung cancer, predominantly in the squamous subtype (Dutt et al. 2011; Weir et al. 2007; Weiss et al. 2010).
Figure 1. Schematic of FGFR signaling pathway. Growth factor binding to FGFR results in activation of the MAPK signaling pathway (RAS-RAF-MEK-ERK). The letter "K" within the schema denotes the tyrosine kinase domain.
Last Updated: June 1, 2012
Amplifications of FGFR1 are predominantly found in squamous cell lung cancers from former/current smokers. The chromosomal region at 8p12 spanning the FGFR1 gene locus is amplified in up to ~20% of squamous cell lung cancer patients. Copy number changes can be detected by various techniques, including fluorescence in situ hybridization (FISH) analysis (Dutt et al. 2011; Turner and Seckl 2010; Weiss et al. 2010); the exact clinically relevant cutoff levels for amplification remain to be determined. In lung cancer patients with other histologies such as adenocarcinoma, FGFR1 amplification is a rare event (less than 2%) (Dutt et al. 2011; Turner and Seckl 2010; Weiss et al. 2010). Preclinical data suggest that cancer cells with amplified FGFR1 can display "addiction" to FGFR signaling.
Last Updated: June 1, 2012
|Frequency of FGFR1 amplification in SCC of the lung||~20% (Dutt et al. 2011; Turner and Seckl 2010; Weiss et al. 2010)|
|Implications for Targeted Therapeutics|
|Response to FGFR inhibitors||Unknown at this timea|
a Tumor cells with FGFR1 amplification are dependent on the activity of the receptor. This dependency can be exploited therapeutically with specific FGFR inhibitors that show promising activity in preclinical models of lung cancer (Dutt et al. 2011; Weiss et al. 2010). A pan-FGFR TKI has been shown to block tumor proliferation and induce apoptosis in a subset of NSCLC cell lines with activated FGFR signaling but has no effect on cells that do not activate the pathway (Marek et al. 2009; Weiss et al. 2010). Clinical trials with FGFR inhibitors are currently underway.
Last Updated: November 15, 2012
Great effort was made to include all clinical trials relevant for this mutation. However, the completeness of this information cannot be guaranteed.
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