Lab 1. Cancer Research Center, Institute of Cancer Molecular and Cellular Biology, CSIC-University of Salamanca and CIBERONC, 37007, Salamanca, Spain.
Institute of Biomedicine of Seville (IBiS)/"Virgen del Rocío" University Hospital/CSIC/University of Seville and Department of Medical Physiology and Biophysics, University of Seville, Seville, Spain.
Nat Commun. 2023 Sep 20;14(1):5856. doi: 10.1038/s41467-023-41583-1.
The impact of genetic ablation of SOS1 or SOS2 is evaluated in a murine model of KRAS-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 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 LUAD tumors. The critical requirement of SOS1 for KRAS-driven LUAD is further confirmed by means of intravenous tail injection of KRAS tumor cells into SOS1/KRAS mice, or of SOS1-less, KRAS 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-driven LUAD and confirm the validity of this RAS-GEF activator as an actionable therapeutic target in KRAS mutant LUAD.
在 KRAS 驱动的肺腺癌 (LUAD) 的小鼠模型中评估 SOS1 或 SOS2 的遗传缺失的影响。SOS2 缺失在早期阶段显示出一些保护作用，但只有 SOS1 缺失导致 KRAS 小鼠的生存/寿命显著、特异性地长期增加，与肺肿瘤微环境 (TME) 中肿瘤负担的显著降低以及癌症相关成纤维细胞、巨噬细胞和 T 淋巴细胞的减少有关。SOS1 缺失还导致预先建立的 KRAS LUAD 肿瘤中的 LUAD 肿瘤肿块和 TME 成分的特异性收缩和消退。通过静脉尾注射 KRAS 肿瘤细胞到 SOS1/KRAS 小鼠中，或 SOS1 缺失的 KRAS 肿瘤细胞到野生型小鼠中，进一步证实了 SOS1 对 KRAS 驱动的 LUAD 的关键要求。对人类肺癌数据库的计算分析也支持 SOS1 在 LUAD 患者的肿瘤发展和生存中具有主导作用。我们的数据表明，SOS1 是 KRAS 驱动的 LUAD 发展所必需的，并证实了这种 RAS-GEF 激活剂作为 KRAS 突变 LUAD 中可操作的治疗靶点的有效性。
