FGFR1 Oncogenic Activation Reveals an Alternative Cell of Origin of SCLC in Rb1/p53 Mice

Abstract

Fibroblast growth factor receptor 1 (FGFR1) is frequently amplified in human small-cell lung cancer (SCLC), but its contribution to SCLC and other lung tumors has remained elusive. Here, we assess the tumorigenic capacity of constitutive-active FGFR1 (FGFR1^K656E) with concomitant RB and P53 depletion in mouse lung. Our results reveal a context-dependent effect of FGFR1^K656E: it impairs SCLC development from CGRP^POS neuroendocrine (NE) cells, which are considered the major cell of origin of SCLC, whereas it promotes SCLC and low-grade NE bronchial lesions from tracheobronchial-basal cells. Moreover, FGFR1^K656E induces lung adenocarcinoma (LADC) from most lung cell compartments. However, its expression is not sustained in LADC originating from CGRP^POS cells. Therefore, cell context and tumor stage should be taken into account when considering FGFR1 inhibition as a therapeutic option.