美国Revolution Medicines公司Mallika Singh等研究人员合作发现，同时抑制致癌型和野生型RAS-GTP能用于治疗癌症。相关论文于2024年4月8日在线发表在《自然》杂志上。

研究人员表示，RAS致癌基因（统称为NRAS、HRAS，尤其是KRAS）是癌症中最常发生突变的基因之一，常见的驱动基因突变发生在密码子12、13和61。KRAS(G12C)癌症蛋白的小分子抑制剂已在多种癌症患者中显示出临床疗效，并已获准用于治疗非小细胞肺癌。尽管如此，KRAS^G12C突变仅占KRAS 突变癌症的15%左右，而对于大多数含有其他常见KRAS突变的肿瘤患者来说，还没有获批的KRAS抑制剂。

研究人员报道了一种可逆的三复合RAS抑制剂RMC-7977，它对突变型和野生型KRAS、NRAS和HRAS变体的活性状态具有广谱活性（一种RAS(ON)多选择性抑制剂）。在临床前研究中，RMC-7977对携带各种RAS基因型的RAS依赖性肿瘤，尤其是对KRAS密码子12突变（KRAS^G12X）的癌症模型具有强效活性。使用RMC-7977治疗可导致肿瘤消退，并且在各种RAS依赖性临床前癌症模型中耐受性良好。

此外，RMC-7977还能抑制KRAS^G12C癌症模型的生长，这些模型由于恢复了RAS通路信号传导而对KRAS(G12C)抑制剂产生耐药性。因此，RAS(ON)多选择性抑制剂可以靶向多种致癌和野生型RAS亚型，有望治疗临床需求尚未得到满足的多种RAS癌症。一种相关的RAS(ON)多选择性抑制剂RMC-6236目前正在对KRAS突变实体瘤患者进行临床评估。

附：英文原文

Title: Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy

Author: Holderfield, Matthew, Lee, Bianca J., Jiang, Jingjing, Tomlinson, Aidan, Seamon, Kyle J., Mira, Alessia, Patrucco, Enrico, Goodhart, Grace, Dilly, Julien, Gindin, Yevgeniy, Dinglasan, Nuntana, Wang, Yingyun, Lai, Lick Pui, Cai, Shurui, Jiang, Lingyan, Nasholm, Nicole, Shifrin, Nataliya, Blaj, Cristina, Shah, Harshit, Evans, James W., Montazer, Nilufar, Lai, Oliver, Shi, Jade, Ahler, Ethan, Quintana, Elsa, Chang, Stephanie, Salvador, Anthony, Marquez, Abby, Cregg, Jim, Liu, Yang, Milin, Anthony, Chen, Anqi, Ziv, Tamar Bar, Parsons, Dylan, Knox, John E., Klomp, Jennifer E., Roth, Jennifer, Rees, Matthew, Ronan, Melissa, Cuevas-Navarro, Antonio, Hu, Feng, Lito, Piro, Santamaria, David, Aguirre, Andrew J., Waters, Andrew M., Der, Channing J., Ambrogio, Chiara, Wang, Zhengping, Gill, Adrian L., Koltun, Elena S., Smith, Jacqueline A. M., Wildes, David, Singh, Mallika

Issue&Volume: 2024-04-08

Abstract: RAS oncogenes (collectively NRAS, HRAS and especially KRAS) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 and 611. Small molecule inhibitors of the KRAS(G12C) oncoprotein have demonstrated clinical efficacy in patients with multiple cancer types and have led to regulatory approvals for the treatment of non-small cell lung cancer2,3. Nevertheless, KRASG12C mutations account for only around 15% of KRAS-mutated cancers4,5, and there are no approved KRAS inhibitors for the majority of patients with tumours containing other common KRAS mutations. Here we describe RMC-7977, a reversible, tri-complex RAS inhibitor with broad-spectrum activity for the active state of both mutant and wild-type KRAS, NRAS and HRAS variants (a RAS(ON) multi-selective inhibitor). Preclinically, RMC-7977 demonstrated potent activity against RAS-addicted tumours carrying various RAS genotypes, particularly against cancer models with KRAS codon 12 mutations (KRASG12X). Treatment with RMC-7977 led to tumour regression and was well tolerated in diverse RAS-addicted preclinical cancer models. Additionally, RMC-7977 inhibited the growth of KRASG12C cancer models that are resistant to KRAS(G12C) inhibitors owing to restoration of RAS pathway signalling. Thus, RAS(ON) multi-selective inhibitors can target multiple oncogenic and wild-type RAS isoforms and have the potential to treat a wide range of RAS-addicted cancers with high unmet clinical need. A related RAS(ON) multi-selective inhibitor, RMC-6236, is currently under clinical evaluation in patients with KRAS-mutant solid tumours (ClinicalTrials.gov identifier: NCT05379985).

DOI: 10.1038/s41586-024-07205-6

Source: https://www.nature.com/articles/s41586-024-07205-6