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A search for anything treatable in squamous lung cancer found extra copies of one growth-factor receptor gene in about a fifth of cases, and cells carrying those extra copies died when the receptor was blocked.
A systematic search across 232 lung cancer specimens for therapeutically amenable genetic alterations, followed by high-resolution copy-number analysis, identified frequent and focal FGFR1 amplification in squamous cell lung cancer (155 cases) but not in other lung cancer subtypes, and fluorescence in situ hybridisation confirmed amplification in 22% of an independent squamous cohort. Screening 83 lung cancer cell lines with the FGFR inhibitor PD173074 showed growth inhibition and apoptosis specifically in FGFR1-amplified cells. Dependence was validated by FGFR1 knockdown and by rescuing amplified cells with an inhibitor-resistant FGFR1 allele, and FGFR1 inhibition produced significant tumour shrinkage in vivo.
It was the first therapeutically tractable alteration found in squamous lung cancer, and in the decade since it has become the standard example of amplification not equalling dependence, because copy number alone has selected patients poorly in trials.
Shares Cytogenetics and FISH, FISH / ISH (in situ hybridisation), Receptor tyrosine kinase activation, Small-molecule kinase inhibitors.
Shares Roman Thomas, Receptor tyrosine kinase activation, Non-small-cell lung cancer.
Shares Gene amplification and copy-number change, Receptor tyrosine kinase activation, Small-molecule kinase inhibitors, Non-small-cell lung cancer.
Shares Gene amplification and copy-number change, FISH / ISH (in situ hybridisation).
Shares FGF / FGFR signalling, Receptor tyrosine kinase activation.
Shares Gene amplification and copy-number change, Receptor tyrosine kinase activation.
Shares Gene amplification and copy-number change, Cytogenetics and FISH, FISH / ISH (in situ hybridisation).
Shares FGFR1, FGF / FGFR signalling, Small-molecule kinase inhibitors.