Pharmacological restoration of GTP hydrolysis by mutant RAS

Antonio Cuevas-Navarro, Yasin Pourfarjam, Feng Hu, Diego J. Rodriguez, Alberto Vides, Ben Sang, Shijie Fan, Yehuda Goldgur, Elisa Stanchina and Piro Lito ()
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Antonio Cuevas-Navarro: Memorial Sloan Kettering Cancer Center
Yasin Pourfarjam: Memorial Sloan Kettering Cancer Center
Feng Hu: Memorial Sloan Kettering Cancer Center
Diego J. Rodriguez: Weill Cornell Medical College and Rockefeller University and Memorial Sloan Kettering Cancer Center
Alberto Vides: Memorial Sloan Kettering Cancer Center
Ben Sang: Memorial Sloan Kettering Cancer Center
Shijie Fan: Memorial Sloan Kettering Cancer Center
Yehuda Goldgur: Memorial Sloan Kettering Cancer Center
Elisa Stanchina: Memorial Sloan Kettering Cancer Center
Piro Lito: Memorial Sloan Kettering Cancer Center

Nature, 2025, vol. 637, issue 8044, 224-229

Abstract: Abstract Approximately 3.4 million patients worldwide are diagnosed each year with cancers that have 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 signalling 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 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 γ-phosphate of GTP in a mutation-specific manner. RAS mutants that were most sensitive to stimulation of GTPase activity were more susceptible to treatment than mutants in which the hydrolysis could not be enhanced, suggesting that pharmacological stimulation of hydrolysis potentiates the therapeutic effects of tri-complex inhibitors for specific RAS mutants. This study lays the foundation for developing a class of therapeutics that inhibit cancer growth by stimulating mutant GTPase activity.

Date: 2025
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DOI: 10.1038/s41586-024-08283-2

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