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 proliferation^3-6. 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 ɣ 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.

每年约有 340 万患者被诊断出患有三种 RAS 原癌基因（KRAS、NRAS 和 HRAS）之一致病突变的癌症^1,2。这些突变会损害 RAS 的 GTP 酶活性，导致下游信号转导激活和增殖^3-6。长期以来恢复 RAS 突变体水解酶活性的努力没有成功，因此消除了对可行治疗策略的任何考虑⁷。在这里，我们表明三复合物抑制剂，即能够将亲环蛋白 A （CYPA） 募集到 RAS 活性状态的分子胶具有双重作用机制：它们不仅阻止活化的 RAS 与其效应子结合，而且出乎意料地，它们还刺激 GTP 水解。药物结合的 CYPA 复合物调节 RAS 开关 II 基序中的残基，以突变特异性方式协调对 GTP 磷酸 ɣ 的亲核攻击。与水解不能增强的突变体相比，对 GTP 酶活性刺激最敏感的 RAS 突变体更容易接受治疗，这表明水解的药物刺激增强了三复合物抑制剂对特定 RAS 突变体的治疗作用。这项研究为开发一类通过刺激突变 GTP 酶活性来抑制癌症生长的新型疗法奠定了基础。