诺华生物医学研究中心Luca Tordella小组报道了靶向RAS突变癌症中的SHOC2-RAS相互作用。2025年5月7日出版的《自然》发表了这项成果。

在这里，该课题组确定了SHOC2，一个SHOC2–MRAS–PP1C复合物的组成部分，作为RAS（Q61*）肿瘤的依赖，以核苷酸状态依赖和异构体不可知的方式。在机制上，该团队发现致癌NRAS（Q61R）与SHOC2形成直接相互作用，X射线共晶结构证明了这一点。体外高通量筛选发现了与SHOC2结合并破坏与NRAS（Q61*）相互作用的小分子。基于结构的优化导致了一种具有细胞活性的工具化合物，在RAS突变癌症模型中，尤其是在NRAS（Q61*）环境中，显示出抑制丝裂原活化蛋白激酶（MAPK）信号传导和增殖的作用。这些发现为新形态的SHOC2 -（规范）RAS蛋白相互作用提供了证据，该相互作用在药理学上是可行的，并且与癌症维持有关。总的来说，这项工作为开发RAS信号通路核心的新疗法提供了概念验证和基础。

据悉，大鼠肉瘤（RAS）基因的激活突变HRAS、NRAS和KRAS共同代表了人类癌症中最常见的致癌驱动因素。它们以前被认为是不可药物的，但在过去几年的进展已经导致靶向KRAS（G12C）和KRAS（G12D）突变体的药物的临床开发，在耐受剂量下产生治疗反应的承诺。然而，选择性靶向NRAS（Q61*）突变体（*代表“any”）的临床药物仍然缺乏，NRAS（Q61*）突变体是黑色素瘤中第二常见的致癌驱动因子。

附：英文原文

Title: Targeting the SHOC2–RAS interaction in RAS-mutant cancers

Author: Hauseman, Zachary J., Stauffer, Frdric, Beyer, Kim S., Moll, Sandra, Cavicchioli, Elena, Marchand, Jean-Remy, Fodor, Michelle, Viscomi, Jessica, Dhembi, Anxhela, Katz, Stphanie, Faggion, Beatrice, Lanter, Mylene, Kerr, Grainne, Schildknecht, Daniela, Handl, Cornelia, Maddalo, Danilo, Pissot Soldermann, Carole, Brady, Jacob, Shrestha, Om, Nguyen, Zachary, Leder, Lukas, Cremosnik, Gregor, Lopez Romero, Sandra, Hassiepen, Ulrich, Stams, Travis, Linder, Markus, Galli, Giorgio G., Guthy, Daniel A., King, Daniel A., Maira, Sauveur-Michel, Thoma, Claudio R., Ehmke, Veronika, Tordella, Luca

Issue&Volume: 2025-05-07

Abstract: Activating mutations in the rat sarcoma (RAS) genes HRAS, NRAS and KRAS collectively represent the most frequent oncogenic driver in human cancer1. They have previously been considered undruggable, but advances in the past few years have led to the clinical development of agents that target KRAS(G12C) and KRAS(G12D) mutants, yielding promises of therapeutic responses at tolerated doses2. However, clinical agents that selectively target NRAS(Q61*) mutants (* represents ‘any’), the second-most-frequent oncogenic driver in melanoma, are still lacking. Here we identify SHOC2, a component of the SHOC2–MRAS–PP1C complex, as a dependency of RAS(Q61*) tumours in a nucleotide-state-dependent and isoform-agnostic manner. Mechanistically, we found that oncogenic NRAS(Q61R) forms a direct interaction with SHOC2, evidenced by X-ray co-crystal structure. In vitro high-throughput screening enabled the discovery of small molecules that bind to SHOC2 and disrupt the interaction with NRAS(Q61*). Structure-based optimization led to a cellularly active tool compound that shows inhibition of mitogen-activated protein kinase (MAPK) signalling and proliferation in RAS-mutant cancer models, most notably in NRAS(Q61*) settings. These findings provide evidence for a neomorph SHOC2–(canonical)RAS protein interaction that is pharmacologically actionable and relevant to cancer sustenance. Overall, this work provides the concept validation and foundation for developing new therapies at the core of the RAS signalling pathway.

DOI: 10.1038/s41586-025-08931-1

Source: https://www.nature.com/articles/s41586-025-08931-1