美国纪念斯隆凯特琳癌症中心Piro Lito团队近期取得重要工作进展，他们研究提出了突变RAS的GTP水解活性的药理学恢复。相关研究成果2024年10月30日在线发表于《自然》杂志上。

据介绍，每年全球约有340万患者被诊断出携带三种RAS原癌基因（KRAS、NRAS和HRAS）之一的致病突变。这些突变会削弱RAS的GTP酶活性，从而激活下游信号传导并促进细胞增殖。长期以来，恢复RAS突变体的水解酶活性一直未取得成功，因此未被视为可行的治疗策略。

研究人员发现了一类三复合物抑制剂，即能够将环孢菌素A（CYPA）招募到RAS活性状态的分子胶，具有双重作用机制：不仅可以防止激活的RAS与其效应分子结合，而且还能刺激GTP水解。

药物结合的CYPA复合物调节RAS的开关II结构域的残基，以协调对GTP的γ磷酸根的亲核攻击，且这种作用是特异性地针对不同的突变。对水解活性最敏感的RAS突变体对治疗的敏感性也更高，而那些水解不能被增强的突变体的治疗效果较差。这表明水解活性的药理学刺激可以增强三复合物抑制剂，对特定RAS突变体的治疗效果。

总之，这一研究成果为开发通过刺激突变GTP酶活性来抑制癌症生长的新型治疗药物奠定了基础。

附：英文原文

Title: Pharmacologic restoration of GTP hydrolysis by mutant RAS

Author: Cuevas-Navarro, Antonio, Pourfarjam, Yasin, Hu, Feng, Rodriguez, Diego J., Vides, Alberto, Sang, Ben, Fan, Shijie, Goldgur, Yehuda, de Stanchina, Elisa, Lito, Piro

Issue&Volume: 2024-10-30

Abstract: Approximately 3.4 million patients worldwide are diagnosed each year with cancers that harbor pathogenic mutations in one of three RAS proto-oncogenes (KRAS, NRAS and HRAS)1,2. These mutations impair the GTPase activity of RAS, leading to activation of downstream signaling and proliferation3-6. Long-standing efforts to restore the hydrolase activity of RAS mutants have been unsuccessful, extinguishing any consideration towards a viable therapeutic strategy7. Here we show that tri-complex inhibitors, that is, molecular glues with the ability to recruit cyclophilin A (CYPA) to the active state of RAS have a dual mechanism of action: not only do they prevent activated RAS from binding to its effectors, but, unexpectedly, they also stimulate GTP hydrolysis. Drug-bound CYPA complexes modulate residues in the switch II motif of RAS to coordinate the nucleophilic attack on the phosphate of GTP, in a mutation-specific manner. RAS mutants most sensitive to stimulation of GTPase activity were more susceptible to treatment compared to mutants whose hydrolysis could not be enhanced, suggesting that pharmacologic stimulation of hydrolysis potentiates the therapeutic effects of tri-complex inhibitors for specific RAS mutants. This study lays the foundation for developing a new class of therapeutics that inhibit cancer growth by stimulating mutant GTPase activity.

DOI: 10.1038/s41586-024-08283-2

Source: https://www.nature.com/articles/s41586-024-08283-2