在KRASG12D驱动的肺腺癌（LUAD）小鼠模型中，评估了SOS1或SOS2的遗传消除对其影响。SOS2消除在早期阶段有一定的保护作用，但只有SOS1消除能显著、特异性地延长KRASG12D小鼠的存活寿命，与明显减少的肿瘤负荷和肺肿瘤微环境（TME）中的癌相关成纤维细胞、巨噬细胞和T淋巴细胞数量减少有关。SOS1消除还导致已建立的KRASG12D LUAD肿瘤中的LUAD肿瘤块和TME组分的特异性收缩和回退。通过将KRASG12D肿瘤细胞静脉尾部注入SOS1KO/KRASWT小鼠或缺乏SOS1的KRASG12D肿瘤细胞注入野生型小鼠，进一步证实了SOS1在KRASG12D驱动的LUAD中的关键要求。人类肺癌数据库的计算机分析也支持SOS1在LUAD患者的肿瘤发展和生存中的主导作用。我们的数据表明，SOS1在KRASG12D驱动的LUAD发展中至关重要，并确认这种RAS-GEF激活剂作为KRAS突变型LUAD中的可行治疗靶点。© 2023. Springer Nature Limited.

The impact of genetic ablation of SOS1 or SOS2 is evaluated in a murine model of KRASG12D-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 KRASG12D 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 KRASG12D LUAD tumors. The critical requirement of SOS1 for KRASG12D-driven LUAD is further confirmed by means of intravenous tail injection of KRASG12D tumor cells into SOS1KO/KRASWT mice, or of SOS1-less, KRASG12D 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 KRASG12D-driven LUAD and confirm the validity of this RAS-GEF activator as an actionable therapeutic target in KRAS mutant LUAD.© 2023. Springer Nature Limited.