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

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.