Inhibition of SHP2 as an approach to block RAS-driven cancers
Inhibition of SHP2 as an approach to block RAS-driven cancers
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DOI：
10.1016/bs.acr.2021.07.002
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发表时间：
2022-01-01
期刊：
影响因子：
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通讯作者：
Bivona, Trever G.
中科院分区：
文献类型：
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作者：
Chou, Yu-Ting;Bivona, Trever G.
非受体蛋白酪氨酸磷酸酶SHP2(由PTPN11编码)是RAS/MAPK信号的重要组成部分，作用于RAS的上游，促进肿瘤信号转导和肿瘤生长。三十多年来，SHP2被认为是“不可用药的”，因为酶活性部位抑制剂通常表现出对其他蛋白质的脱靶抑制和低膜透过性。最近，具有显著抑制作用的变构SHP2抑制剂已经被开发出来。这些小分子有效地阻断了受体酪氨酸激酶(RTK)和RAS/MAPK信号之间的信号转导，并在临床前癌症模型中显示出有效性。此外，对这些变构SHP2抑制剂的临床评估正在进行中。通过功能获得突变而具有转化特性的RAS蛋白存在于各种癌症类型中。虽然KRASG12C的抑制剂显示出早期的临床前景，但耐药性仍然是一个挑战，其他形式的致癌RAS仍有待选择性地抑制。在这里，我们总结了SHP2在RAS驱动的癌症中的作用，以及变构SHP2抑制剂作为阻断RAS驱动的癌症的策略的治疗潜力。
The non-receptor protein tyrosine phosphatase SHP2 (encoded by PTPN11) is a critical component of RAS/MAPK signaling by acting upstream of RAS to promote oncogenic signaling and tumor growth. Over three decades, SHP2 was considered "undruggable" because enzymatic active-site inhibitors generally showed off-target inhibition of other proteins and low membrane permeability. More recently, allosteric SHP2 inhibitors with striking inhibitory potency have been developed. These small molecules effectively block the signal transduction between receptor tyrosine kinases (RTKs) and RAS/MAPK signaling and show efficacy in preclinical cancer models. Moreover, clinical evaluation of these allosteric SHP2 inhibitors is ongoing. RAS proteins which harbor transforming properties by gain-of-function mutations are present in various cancer types. While inhibitors of KRASG12C show early clinical promise, resistance remains a challenge and other forms of oncogenic RAS remain to be selectively inhibited. Here, we summarize the role of SHP2 in RAS-driven cancers and the therapeutic potential of allosteric SHP2 inhibitors as a strategy to block RAS-driven cancers.