Oncogenic role of FGFR1 and vulnerability of RBL2-FGFR1 axis in small cell lung cancer development

Abstract

Abstract The observation of recurrent fibroblast growth factor receptor 1 (FGFR1) amplification in small cell lung cancer (SCLC) raised the possibility of targeting the FGFR1 pathway to treat this aggressive disease. However, in vivo evidence for the significance of FGFR1 in SCLC development is lacking, and previous studies indicate a need for additional biomarkers to stratify patient tumours for anti-FGFR1 therapeutics. Here, we found that ectopic Fgfr1 expression in precancerous neuroendocrine cells (preSCs) increased cell growth in vitro and tumour formation in immune-compromised mice, results that coincided with transcriptomic changes indicative of altered differentiation and enhanced proliferation. Interestingly, Fgfr1 deletion suppressed tumour development in Rb1/Trp53/Rbl2-mutant mice but not in Rb1/Trp53-mutant mice. This Rbl2-dependent difference in phenotype suggests a functional link between this well-known tumour suppressor and FGFR1 signalling during SCLC development. Rbl2 knockout in preSCs selectively increased Fgfr1 expression while promoting tumour formation. Rbl2 loss also correlated with Fgfr1 induction in allograft tumours generated from preSCs carrying oncogenic mutations and primary tumours developed in the Rb1/Trp53-mutant mouse model. These results demonstrate the importance of enhanced FGFR1 and the vulnerability of the RBL2-FGFR1 axis for SCLC development.