Critical requirement of SOS1 for tumor development and microenvironment modulation in KRAS^G12D-driven lung adenocarcinoma.

Abstract

The impact of genetic ablation of SOS1 or SOS2 is evaluated in a murine model of KRAS^G12D-driven lung adenocarcinoma (LUAD). SOS2 ablation shows some protection during early stages but only SOS1 ablation causes significant, specific long term increase of survival/lifespan of the KRAS^G12D mice associated to markedly reduced tumor burden and reduced populations of cancer-associated fibroblasts, macrophages and T-lymphocytes in the lung tumor microenvironment (TME). SOS1 ablation also causes specific shrinkage and regression of LUAD tumoral masses and components of the TME in pre-established KRAS^G12D LUAD tumors. The critical requirement of SOS1 for KRAS^G12D-driven LUAD is further confirmed by means of intravenous tail injection of KRAS^G12D tumor cells into SOS1^KO/KRAS^WT mice, or of SOS1-less, KRAS^G12D tumor cells into wildtype mice. In silico analyses of human lung cancer databases support also the dominant role of SOS1 regarding tumor development and survival in LUAD patients. Our data indicate that SOS1 is critically required for development of KRAS^G12D-driven LUAD and confirm the validity of this RAS-GEF activator as an actionable therapeutic target in KRAS mutant LUAD.