Frequent and Focal FGFR1 Amplification Associates with Therapeutically Tractable FGFR1 Dependency in Squamous Cell Lung Cancer

Abstract

Lung cancer remains one of the leading causes for cancer-related death in developed countries. In lung adenocarcinomas, EGFR mutations and EML4-ALK fusions are associated with response to EGFR and ALK inhibition. By contrast, therapeutically exploitable genetic alterations have been lacking in squamous-cell lung cancer. We conducted a systematic search for alterations that are therapeutically amenable and performed high-resolution gene-copy number analyses in a set of 232 lung cancer specimens. We identified frequent and focal FGFR1 amplification in squamous-cell lung cancer (n=155), but not in other lung cancer subtypes, and confirmed its presence in an independent cohort of squamous-cell lung cancer samples employing FISH (22% of cases). Using cell-based screening with the FGFR inhibitor (PD173074) in a large (n=83) panel of lung cancer cell lines, we demonstrated that this compound inhibited growth (p=0.0002) and induced apoptosis (p=0.008) specifically in those lung cancer cells carrying amplified FGFR1. We validated the dependency on FGFR1 of FGFR1-amplified cell lines by knockdown of FGFR1 and by ectopic expression of a resistance allele of FGFR1 (FGFR1V561M), which rescued FGFR1-amplified cells from PD173074-mediated cytotoxicity. Finally we showed that inhibition of FGFR1 with a small molecule led to significant tumor shrinkage in vivo. Focal FGFR1 amplification is common in squamous-cell lung cancer and associated with tumor growth and survival, suggesting that FGFR inhibitors may be a viable therapeutic option in this cohort of patients.

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

“…Low amplification level (as defined by absence of criteria for high-level amplification and Z5 FGFR1 signals in Z50% of tumor cells) occurred only once in our cohort and accounts for 0.4% of all evaluable FISH-positive cases (n ¼ 251), but 5.2% of small-cell carcinomas (92% of FISH-positive tumors) show high-level amplification (as defined by an FGFR1/CEN8 Z2.0, or average number of FGFR1 signals per tumor cell nucleus Z6, or the percentage of tumor cells containing Z15 FGFR1 signals or large clusters Z10%). 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.…”

“…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.…”

“…1 Over the last 30 years, medical treatment for advanced SCLC has mainly remained unchanged, consisting of a platinum-based chemotherapy regimen with optional radiation therapy depending on tumor stage. 2 Although targeted therapeutic options have been established for pulmonary adenocarcinomas, including EGFR (epidermal growth factor receptor) and ALK (anaplastic lymphoma kinase) inhibitors, 1,3,4 and recently also for squamous cell carcinomas, 5,6 small-cell carcinomas still lack therapeutically exploitable genetic alterations. So far no single molecularly targeted drug has yet shown any significant clinical activity in SCLC.…”

“…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

“…12,13 Soon after, Weiss et al 14 identified FGFR1 amplification as an actionable target in squamous cell carcinoma of the lung. 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.…”