Pharmacological restoration of GTP hydrolysis by mutant RAS Journal Article
| Authors: | Cuevas-Navarro, A.; Pourfarjam, Y.; Hu, F.; Rodriguez, D. J.; Vides, A.; Sang, B.; Fan, S.; Goldgur, Y.; de Stanchina, E.; Lito, P. |
| Article Title: | Pharmacological restoration of GTP hydrolysis by mutant RAS |
| 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, 4, 5–6. 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. © The Author(s) 2024. |
| Keywords: | controlled study; protein expression; unclassified drug; gene mutation; human cell; mutation; nonhuman; antineoplastic agent; mouse; cell viability; animal experiment; animal model; enzyme activity; inhibitor; protein purification; gefitinib; immunoblotting; crystal structure; tumor growth; structure analysis; guanosine triphosphate; hydrolysis; oncogene ras; autoradiography; crystallography; guanosine triphosphatase; drug; cyclophilin a; pathogen; trametinib; cancer; human; article; affinity purification; hek293t cell line; bi 3406; rmc 6236; rmc 4550; rmc 4998; rmc 7977 |
| Journal Title: | Nature |
| Volume: | 637 |
| Issue: | 8044 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2025-01-02 |
| Start Page: | 224 |
| End Page: | 229 |
| Language: | English |
| DOI: | 10.1038/s41586-024-08283-2 |
| PUBMED: | 39476862 |
| PROVIDER: | scopus |
| PMCID: | PMC11666464 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Piro Lito -- Source: Scopus |
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