Abstract A20: FGFR1-amplified squamous cell lung cancers depend on FGFR1

Abstract

Abstract In lung adenocarcinomas of never-smokers EGFR mutations or EML4-ALK gene fusions are frequent genomic events that both expose prime therapeutic targets. By contrast, squamous cell lung cancer (SQLC) is almost invariably associated with smoking; in this subgroup of patients, no attractive therapeutic target has so far been identified. In order to identify such a therapeutically exploitable target in SQLC, we performed high-resolution genomic analyses of over 300 lung tumor specimens. Using 6.0 Affymetrix SNP-arrays we identified high-level focal amplifications of FGFR1 in 10% of over 150 primary SQLC specimens. Importantly, FGFR1 amplification was almost exclusively restricted to SQLC of smokers and almost never observed in adenocarcinomas. We also performed high-throughput cell line screening of 82 genomically annotated lung cancer cell lines using the FGFR inhibitor PD170374 and identified the presence of focal FGFR1 -amplifications as the strongest predictor of PD170374 activity. Biochemical kinase profiling across 108 kinases suggested that PD170374 was highly selective with only one of the kinases being inhibited to a similar extend as FGFR1 itself. Treatment with PD173074 induced apoptosis and inhibited MAPK- and, to a lesser extend, PI3K signaling in cell lines with focal amplification of FGFR1. In order to validate FGFR1 as a critical target in FGFR1 -amplified cells we employed retroviral expression of the gatekeeper mutant allele of FGFR1 (V561M) and thus the PD173074-sensitive cells were rendered resistant. Additionally, lentiviral-mediated knockdown of FGFR1 in FGFR1 -amplified cell lines confirmed FGFR1 as a critical target for FGFR1 inhibition in these cells. Finally, successful treatment of mice engrafted with FGFR1 -amplified lung cancer cell lines with PD173074 confirmed its on-target activity in vivo. Overall, our work demonstrates the functional relevance of amplification of FGFR1 in lung cancer and suggests that inhibition of FGFR with targeted therapeutics might be an effective strategy in squamous cell carcinoma patients with focal amplification of FGFR1. Citation Information: Clin Cancer Res 2010;16(14 Suppl):A20.