Hauseman Zachary J, Stauffer Frédéric, Beyer Kim S, Mollé Sandra, Cavicchioli Elena, Marchand Jean-Remy, Fodor Michelle, Viscomi Jessica, Dhembi Anxhela, Katz Stéphanie, 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
Novartis BioMedical Research, Cambridge, MA, USA.
Novartis BioMedical Research, Basel, Switzerland.
Nature. 2025 May 7. doi: 10.1038/s41586-025-08931-1.
Activating mutations in the rat sarcoma (RAS) genes HRAS, NRAS and KRAS collectively represent the most frequent oncogenic driver in human cancer. 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 doses. 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.
大鼠肉瘤（RAS）基因HRAS、NRAS和KRAS中的激活突变共同构成了人类癌症中最常见的致癌驱动因素。它们此前被认为是不可成药的，但过去几年的进展已促使针对KRAS（G12C）和KRAS（G12D）突变体的药物进入临床开发阶段，有望在耐受剂量下产生治疗反应。然而，仍缺乏能够选择性靶向NRAS（Q61*）突变体（代表“任意”）的临床药物，NRAS（Q61）突变体是黑色素瘤中第二常见的致癌驱动因素。在此，我们确定了SHOC2-MRAS-PP1C复合物的一个组成部分SHOC2，它以核苷酸状态依赖且异构体无关的方式成为RAS（Q61*）肿瘤的一个依赖因素。从机制上讲，我们发现致癌性NRAS（Q61R）与SHOC2形成直接相互作用，X射线共晶体结构证明了这一点。体外高通量筛选促使发现了与SHOC2结合并破坏其与NRAS（Q61*）相互作用的小分子。基于结构的优化产生了一种具有细胞活性的工具化合物，该化合物在RAS突变癌症模型中显示出对丝裂原活化蛋白激酶（MAPK）信号传导和增殖的抑制作用，在NRAS（Q61*）环境中尤为明显。这些发现为一种新形态的SHOC2-（经典）RAS蛋白相互作用提供了证据，这种相互作用在药理学上是可作用的，并且与癌症维持相关。总体而言，这项工作为在RAS信号通路核心开发新疗法提供了概念验证和基础。
