The 8p12 locus (containing the FGFR1 tyrosine kinase gene) is frequently amplified in squamous-cell lung cancer (SQLC). However, it is currently unknown, which of the 8p12-amplified tumors are also sensitive to FGFR inhibition. We found that, in contrast to other recurrent amplifications, the 8p12 region included multiple centers of amplification, suggesting marked genomic heterogeneity. FGFR1-amplified tumor cells were dependent on FGFR ligands in vitro and in vivo. Furthermore, ectopic expression of FGFR1 was oncogenic, which was enhanced by expression of MYC. We found that MYC was co-expressed in 40% of FGFR1-amplified tumors. Tumor cells co-expressing MYC were more sensitive to FGFR inhibition, suggesting that patients with FGFR1-amplified and MYC-overexpressing tumors may benefit from FGFR inhibitor therapy. Thus, both cell-autonomous and non-cell-autonomous mechanisms of transformation modulate FGFR dependency in FGFR1-amplified lung cancer, which may have implications for patient selection for treatment with FGFR inhibitors.

Read more »