Department of Medicine, Division of Hematology and Oncology, and The Helen Diller Comprehensive Cancer Center, University of California, San Francisco, CA, United States.
Department of Medicine, Division of Hematology and Oncology, and The Helen Diller Comprehensive Cancer Center, University of California, San Francisco, CA, United States.
Adv Cancer Res. 2022;153:205-236. doi: 10.1016/bs.acr.2021.07.002. Epub 2021 Aug 3.
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.
非受体酪氨酸蛋白磷酸酶 SHP2（由 PTPN11 编码）是 RAS/MAPK 信号通路的关键组成部分，通过作用于 RAS 的上游促进致癌信号和肿瘤生长。三十多年来，由于酶活性位点抑制剂通常会对其他蛋白质产生非靶向抑制作用和低膜通透性，因此 SHP2 被认为是“不可成药”的。最近，已经开发出具有惊人抑制效力的别构 SHP2 抑制剂。这些小分子有效地阻断了受体酪氨酸激酶（RTKs）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疗效。此外，这些别构 SHP2 抑制剂的临床评估正在进行中。RAS 蛋白通过获得功能突变而具有转化特性，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，其他形式的致癌性 RAS 仍有待选择性抑制。在这里，我们总结了 SHP2 在 RAS 驱动的癌症中的作用，以及别构 SHP2 抑制剂作为阻断 RAS 驱动的癌症的治疗策略的潜在作用。
