历史上，KRAS 一直被认为是“不可成药”的，尽管它是实体瘤中最常改变的致癌蛋白之一，这主要是由于突变亚型内缺乏药理学上“可成药”的口袋。然而，能够针对突变 KRAS 亚型（尤其是 KRASG12C 突变癌症）的药物设计的开创性发展，为出现由多种针对不同信号通路的抑制剂组成的联合疗法打开了大门。 SHP2 信号通路主要以激活 KRAS 等细胞内信号通路而闻名，已成为此类联合疗法的潜在靶标，因为它是连接 KRAS 和免疫信号通路的信号蛋白，并为理解重叠区域提供了链接RAS/ERK/MAPK 信号级联反应。因此，具有强大杀肿瘤活性以及免疫调节作用的SHP2抑制剂引起了研究人员的浓厚兴趣，以探索其作为KRAS突变实体瘤联合疗法的潜力。然而，这些联合疗法的兴奋需要克服耐药性和毒性增强带来的挑战。在这篇综述中，我们将讨论 KRAS 和 SHP2 信号通路及其在免疫调节和肿瘤微环境调节中的作用，并分析针对这些信号通路的不同联合疗法的积极作用和缺点，以及它们目前和未来治疗实体瘤的潜力。肿瘤。版权所有 © 2024。由 Elsevier Inc. 出版。

Historically, KRAS has been considered 'undruggable' inspite of being one of the most frequently altered oncogenic proteins in solid tumors, primarily due to the paucity of pharmacologically 'druggable' pockets within the mutant isoforms. However, pioneering developments in drug design capable of targeting the mutant KRAS isoforms especially KRASG12C-mutant cancers, have opened the doors for emergence of combination therapies comprising of a plethora of inhibitors targeting different signaling pathways. SHP2 signaling pathway, primarily known for activation of intracellular signaling pathways such as KRAS has come up as a potential target for such combination therapies as it emerged to be the signaling protein connecting KRAS and the immune signaling pathways and providing the link for understanding the overlapping regions of RAS/ERK/MAPK signaling cascade. Thus, SHP2 inhibitors having potent tumoricidal activity as well as role in immunomodulation have generated keen interest in researchers to explore its potential as combination therapy in KRAS mutant solid tumors. However, the excitement with these combination therapies need to overcome challenges thrown up by drug resistance and enhanced toxicity. In this review, we will discuss KRAS and SHP2 signaling pathways and their roles in immunomodulation and regulation of tumor microenvironment and also analyze the positive effects and drawbacks of the different combination therapies targeted at these signaling pathways along with their present and future potential to treat solid tumors.Copyright © 2024. Published by Elsevier Inc.