FGFR1 is critical for Rbl2 loss-driven tumor development and requires PLCG1 activation for continued growth of small cell lung cancer

Abstract

Small cell lung cancer (SCLC) remains a recalcitrant disease; limited therapeutic options have not improved overall survival and approved targeted therapies are lacking. Amplification of the tyrosine kinase receptor FGFR1 (fibroblast growth factor receptor 1) is one of the few actionable alterations found in SCLC genome. However, efforts to develop targeted therapies for FGFR1-amplified SCLC are hindered by critical gaps in knowledge around the molecular origins and mediator of FGFR1-driven signalling and the physiological impact of targeting FGFR1. Here we demonstrate the oncogenic impact of increased FGFR1 on the malignant progression of precancerous cells and the necessity of nonamplified FGFR1 for SCLC development and homeostasis. Unexpected dependency of Rbl2 loss-driven tumor development on FGFR1 in autochthonous mouse models reveals a novel function of p130 (encoded by Rbl2), a member of the RB family of tumor suppressors, as a regulator of FGFR1 expression. Additionally, FGFR1-dependent SCLC cells require activation of PLCG1 for continued growth. Together, this study uncovers mechanisms of FGFR1-driven SCLC that involves p130 upstream and PLCG1 downstream and provides potential biomarkers for anti-FGFR1 therapeutic strategy.