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 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.

Nature, Published: 30 October 2024