文章：

通过SHP2抑制在癌症与免疫细胞中克服免疫检查点疗法耐药性：文献综述与新型联合策略

Overcoming Immune Checkpoint Therapy Resistance with SHP2 Inhibition in Cancer and Immune Cells: A Review of the Literature and Novel Combinatorial Approaches

原文发布日期：13 November 2023

DOI: 10.3390/cancers15225384

类型: Article

开放获取: 是

英文摘要：

SHP2 (Src Homology 2 Domain-Containing Phosphatase 2) is a protein tyrosine phosphatase widely expressed in various cell types. SHP2 plays a crucial role in different cellular processes, such as cell proliferation, differentiation, and survival. Aberrant activation of SHP2 has been implicated in multiple human cancers and is considered a promising therapeutic target for treating these malignancies. The PTPN11 gene and functions encode SHP2 as a critical signal transduction regulator that interacts with key signaling molecules in both the RAS/ERK and PD-1/PD-L1 pathways; SHP2 is also implicated in T-cell signaling. SHP2 may be inhibited by molecules that cause allosteric (bind to sites other than the active site and attenuate activation) or orthosteric (bind to the active site and stop activation) inhibition or via potent SHP2 degraders. These inhibitors have anti-proliferative effects in cancer cells and suppress tumor growth in preclinical models. In addition, several SHP2 inhibitors are currently in clinical trials for cancer treatment. This review aims to provide an overview of the current research on SHP2 inhibitors, including their mechanism of action, structure-activity relationships, and clinical development, focusing on immune modulation effects and novel therapeutic strategies in the immune-oncology field.

摘要翻译： 

SHP2（含Src同源2结构域蛋白酪氨酸磷酸酶2）是一种广泛表达于多种细胞类型的蛋白酪氨酸磷酸酶。SHP2在细胞增殖、分化及存活等多种细胞过程中发挥关键作用。SHP2的异常活化与多种人类癌症密切相关，被认为是治疗这些恶性肿瘤的重要潜在靶点。PTPN11基因编码的SHP2作为关键信号转导调节因子，在RAS/ERK和PD-1/PD-L1通路中与核心信号分子相互作用，并参与T细胞信号传导。SHP2可通过变构抑制（结合活性位点以外的区域减弱激活）、正构抑制（结合活性位点阻断激活）或高效降解剂等多种分子机制被抑制。这些抑制剂在癌细胞中具有抗增殖效应，并在临床前模型中能抑制肿瘤生长。目前已有多种SHP2抑制剂进入癌症治疗的临床试验阶段。本综述旨在系统阐述SHP2抑制剂的研究现状，包括其作用机制、构效关系及临床研发进展，重点关注其在免疫调节效应及肿瘤免疫治疗领域的新型治疗策略。

原文链接：

Overcoming Immune Checkpoint Therapy Resistance with SHP2 Inhibition in Cancer and Immune Cells: A Review of the Literature and Novel Combinatorial Approaches