Department of Biology, Revolution Medicines, Inc., Redwood City, CA, USA.
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Nat Cell Biol. 2018 Sep;20(9):1064-1073. doi: 10.1038/s41556-018-0169-1. Epub 2018 Aug 13.
Oncogenic alterations in the RAS/RAF/MEK/ERK pathway drive the growth of a wide spectrum of cancers. While BRAF and MEK inhibitors are efficacious against BRAF-driven cancers, effective targeted therapies are lacking for most cancers driven by other pathway alterations, including non-V600E oncogenic BRAF, RAS GTPase-activating protein (GAP) NF1 (neurofibromin 1) loss and oncogenic KRAS. Here, we show that targeting the SHP2 phosphatase (encoded by PTPN11) with RMC-4550, a small-molecule allosteric inhibitor, is effective in human cancer models bearing RAS-GTP-dependent oncogenic BRAF (for example, class 3 BRAF mutants), NF1 loss or nucleotide-cycling oncogenic RAS (for example, KRAS). SHP2 inhibitor treatment decreases oncogenic RAS/RAF/MEK/ERK signalling and cancer growth by disrupting SOS1-mediated RAS-GTP loading. Our findings illuminate a critical function for SHP2 in promoting oncogenic RAS/MAPK pathway activation in cancers with RAS-GTP-dependent oncogenic BRAF, NF1 loss and nucleotide-cycling oncogenic KRAS. SHP2 inhibition is a promising molecular therapeutic strategy for patients with cancers bearing these oncogenic drivers.
致癌性 RAS/RAF/MEK/ERK 通路改变驱动广泛的癌症生长。虽然 BRAF 和 MEK 抑制剂对 BRAF 驱动的癌症有效，但对于大多数由其他通路改变驱动的癌症，包括非 V600E 致癌 BRAF、RAS GTP 酶激活蛋白（GAP）NF1（神经纤维瘤 1）缺失和致癌性 KRAS，缺乏有效的靶向治疗。在这里，我们表明，用小分子变构抑制剂 RMC-4550 靶向 SHP2 磷酸酶（由 PTPN11 编码），在携带 RAS-GTP 依赖性致癌性 BRAF（例如，3 类 BRAF 突变体）、NF1 缺失或核苷酸循环致癌性 RAS（例如，KRAS）的人类癌症模型中是有效的。SHP2 抑制剂治疗通过破坏 SOS1 介导的 RAS-GTP 加载来减少致癌性 RAS/RAF/MEK/ERK 信号传导和癌症生长。我们的发现阐明了 SHP2 在促进依赖 RAS-GTP 的致癌性 BRAF、NF1 缺失和核苷酸循环致癌性 KRAS 的癌症中激活致癌性 RAS/MAPK 通路中的关键功能。SHP2 抑制是携带这些致癌驱动因素的癌症患者的一种有前途的分子治疗策略。
