以 KRAS 和 SHP2 信号通路为靶点进行免疫调节,改善实体瘤的治疗效果。

3区 生物学 Q1 Biochemistry, Genetics and Molecular Biology
Priyanka Sahu, Ankita Mitra, Anirban Ganguly
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引用次数: 0

摘要

尽管 KRAS 是实体瘤中最常发生变化的致癌蛋白之一,但它一直被认为是 "不可药用 "的,这主要是由于突变异构体中的药理学 "可药用 "口袋极少。然而,能够靶向突变 KRAS 异构体(尤其是 KRASG12C 突变癌症)的药物设计的开创性发展,为由大量靶向不同信号通路的抑制剂组成的联合疗法的出现打开了大门。SHP2 信号通路主要用于激活 KRAS 等细胞内信号通路,现已成为此类联合疗法的潜在靶点,因为它是连接 KRAS 和免疫信号通路的信号蛋白,为了解 RAS/ERK/MAPK 信号级联的重叠区域提供了纽带。因此,具有强效杀瘤活性和免疫调节作用的 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,这些令人兴奋的联合疗法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控中的作用,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。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Targeting KRAS and SHP2 signaling pathways for immunomodulation and improving treatment outcomes in solid tumors.

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.

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来源期刊
International review of cell and molecular biology
International review of cell and molecular biology BIOCHEMISTRY & MOLECULAR BIOLOGY-CELL BIOLOGY
CiteScore
7.70
自引率
0.00%
发文量
67
审稿时长
>12 weeks
期刊介绍: International Review of Cell and Molecular Biology presents current advances and comprehensive reviews in cell biology-both plant and animal. Articles address structure and control of gene expression, nucleocytoplasmic interactions, control of cell development and differentiation, and cell transformation and growth. Authored by some of the foremost scientists in the field, each volume provides up-to-date information and directions for future research.
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