Inhibitor-Sensitive FGFR1 Amplification in Human Non-Small Cell Lung Cancer

Abstract

BackgroundSquamous cell lung carcinomas account for approximately 25% of new lung carcinoma cases and 40,000 deaths per year in the United States. Although there are multiple genomically targeted therapies for lung adenocarcinoma, none has yet been reported in squamous cell lung carcinoma.Methodology/Principal FindingsUsing SNP array analysis, we found that a region of chromosome segment 8p11-12 containing three genes–WHSC1L1, LETM2, and FGFR1–is amplified in 3% of lung adenocarcinomas and 21% of squamous cell lung carcinomas. Furthermore, we demonstrated that a non-small cell lung carcinoma cell line harboring focal amplification of FGFR1 is dependent on FGFR1 activity for cell growth, as treatment of this cell line either with FGFR1-specific shRNAs or with FGFR small molecule enzymatic inhibitors leads to cell growth inhibition.Conclusions/SignificanceThese studies show that FGFR1 amplification is common in squamous cell lung cancer, and that FGFR1 may represent a promising therapeutic target in non-small cell lung cancer.

Fibroblast growth factor receptor 1 (FGFR1) amplification is a potential therapeutic target in small-cell lung cancer

“…5,6,15,17 This is a clinically important finding since until now current therapies are very limited. So far no positive data about FGFR1 FISH analysis in SCLC have been described in the literature.…”

“…Previous data suggest that cancer cell lines with high-level amplification respond better to treatment with FGFR inhibitors, 6 which was also confirmed in an independent study. 15 Therefore, it may be expected that tumors with high-level FGFR1 amplification will respond better to treatment with FGFR inhibitors.…”

“…Our group could show an oncogene dependency for a focal FGFR1 amplification in a large subset of pulmonary carcinomas, a finding that was reproduced by subsequent studies. 5,6,15 Furthermore, FGFR1 amplification represents a therapeutically tractable molecular event, as a selective inhibitor of the FGFR activity caused G1 growth arrest in breast cancer cell lines. 10 In SCLC, inhibition of the FGFR resulted in blockade of tumor growth, suggesting the important role of the FGF-FGFR signaling pathway for SCLC growth 16 and a recent survey of potential oncogenic driver mutations also suggested FGFR1 as a potential therapeutic target.…”

Fibroblast growth factor receptor 1 amplification is a common event in squamous cell carcinoma of the head and neck

“…We and others previously discovered the highly smoking-related FGFR1 amplification in approximately a fifth of all primary squamous cell lung cancer. 14,15 This discovery resulted in the immediate initiation of a phase I clinical trial of small-molecule FGFR inhibitor therapy that is enrolling patients diagnosed with stage IV disease suffering from the second recurrence with FGFR1-amplified primary squamous cell lung cancer.…”

“…14 Of note, FGFR inhibitors in use for clinical trails are not specific to a particular FGFR. The treatment of patients with lung cancer is currently the subject of clinical trials based on FGFR1 amplification, and also based on the fact that both studies mentioned above and also others were able to demonstrate an oncogenic addiction to FGFR1 signaling of FGFR1-amplified cells, which are highly specific to inhibition with pan-FGFR inhibitors, [14][15][16] as cells were sensitive to pan-FGFR inhibitors, although FGFR2-4 were not relevantly expressed. 17 We recently described FGFR1 amplifications in regional lymph node metastases of FGFR1-amplified squamous cell lung cancer, broadening the rationale for therapy with these small-molecule inhibitors to the setting of metastatic disease.…”