Frequent and Focal FGFR1 Amplification Associates With Therapeutically Tractable FGFR1 Dependency in Squamous-cell Lung Cancer

By J. Weiss, M. Sos, D. Seidel, M. Peifer, T. Zander, J. Heuckmann, R. Ullrich, R. Menon, Sebastian Maier, A. Soltermann and 52 more. Science Translational Medicine, 2010

861 citations recorded by the source corpus.

FGFR1 amplification provides a therapeutic target for squamous cell lung cancer, which is resistant to other targeted lung cancer drugs. A Smoking Gun for Lung Cancer Detectives and scientists alike need strong evidence to take their cases to the judge, who for scientists is often a patient with a deadly disease. Yet, new culprits are sometimes found that can break a case wide open. Lung cancer, which accounts for more than 10% of the global cancer burden, has a poor prognosis and inadequately responds to chemotherapy and radiotherapy. New targeted treatments for lung adenocarcinomas inhibit the oncogenic versions of signaling protein kinases that arise from mutations typically found in lung cancer patients who have never smoked. However, smokers frequently suffer from a different deviant, squamous cell lung cancers, for which there are no known molecular genetic targets for therapy. Now, Weiss et al. have fingered a new suspect in smoking-related lung cancer: amplification of the FGFR1 gene, which encodes the fibroblast growth factor receptor 1 tyrosine kinase (FGFR1). To identify therapeutically viable genetic alterations that may influence squamous cell lung cancer, Weiss et al. performed genomic profiles on a large set of lung cancer specimens. Squamous cell lung cancer samples showed FGFR1 amplification, which was not found in other lung cancer subtypes. The authors then determined that a molecule that broadly inhibits FGF receptor function could block tumor growth and cause cell death in the cancers that expressed high amounts of the FGFR1 gene product in a manner that was dependent on FGFR1 expression. Moreover, FGFR1 inhibition resulted in a considerable decrease in tumor size in a mouse model of FGFR1-amplified lung cancer. This culmination of evidence implies that inhibition of this receptor tyrosine kinase should be explored as a candidate therapy for corralling squamous cell lung cancer in smokers. Lung cancer remains one of the leading causes of cancer-related death in developed countries. Although lung adenocarcinomas with EGFR mutations or EML4-ALK fusions respond to treatment by epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibition, respectively, squamous cell lung cancer currently lacks therapeutically exploitable genetic alterations. We conducted a systematic search in a set of 232 lung cancer specimens for genetic alterations that were therapeutically amenable and then performed high-resolution gene copy number analyses. We identified frequent and focal fibroblast growth factor receptor 1 (FGFR1) amplification in squamous cell lung cancer (n = 155), but not in other lung cancer subtypes, and, by fluorescence in situ hybridization, confirmed the presence of FGFR1 amplifications in an independent cohort of squamous cell lung cancer samples (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 and induced apoptosis specifically in those lung cancer cells carrying amplified FGFR1. We validated the FGFR1 dependence of FGFR1-amplified cell lines by FGFR1 knockdown and by ectopic expression of an FGFR1-resistant allele (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. Thus, 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.

Subfields: Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/770683e31568fe1751b83b49c763e8b000109c1e

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Citations in the corpus

• Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma (2013, neutral): “FGFR1 is more commonly activated through amplification in tumors such as breast 28 and lung 29,30 cancer.”
• Emergence of FGFR family gene fusions as therapeutic targets in a wide spectrum of solid tumours (2014, background): “FGFR1 amplifications have been observed in breast [22] and lung cancers [23], whereas aberrant FGFR2 signalling is implicated in endometrial [24], breast [25], and gastric cancers [26].”
• Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas (2014, background): “Therapeutic implications for these particular changes are being investigated clinically and preclinically (33, 40, 41).”
• The FGFR Landscape in Cancer: Analysis of 4,853 Tumors by Next-Generation Sequencing (2015, background): “Others (20, 21, 40, 41) also reported high rates of FGFR1 amplification in squamous cell lung cancer (13%–22%).”
• Lessons from the cancer genome. (2013, neutral): “FGFR1 was found to be amplified in >20% of lung squamous cancer (Weiss et al., 2010) and in 10% of breast cancers (Chin et al.”