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Updated: Jun 9, 2025
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Detection of Small GTPase Prenylation and GTP Binding Using Membrane Fractionation and GTPase-linked Immunosorbent Assay
Published on: November 11, 2018
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Pharmacological restoration of GTP hydrolysis by mutant RAS
Antonio Cuevas-Navarro1, Yasin Pourfarjam1, Feng Hu1
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nature
|October 30, 2024
Summary
New tri-complex inhibitors offer a novel therapeutic strategy for RAS-mutated cancers by restoring GTPase activity. These molecular glues recruit cyclophilin A (CYPA) to stimulate GTP hydrolysis, inhibiting cancer cell proliferation.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- RAS proto-oncogenes (KRAS, NRAS, HRAS) are frequently mutated in approximately 3.4 million cancer patients annually.
- Mutations in RAS impair GTPase activity, leading to uncontrolled cell signaling and proliferation.
- Previous therapeutic strategies targeting RAS mutants have been unsuccessful.
Purpose of the Study:
- To investigate the potential of tri-complex inhibitors as a novel therapeutic approach for RAS-mutated cancers.
- To elucidate the dual mechanism of action of these inhibitors.
Main Methods:
- Utilized tri-complex inhibitors designed to recruit cyclophilin A (CYPA) to the active state of RAS.
- Investigated the effect of these inhibitors on RAS effector binding and GTP hydrolysis.
- Analyzed the mutation-specific modulation of RAS residues by drug-bound CYPA complexes.
Main Results:
- Tri-complex inhibitors demonstrated a dual mechanism: inhibiting RAS effector binding and stimulating GTP hydrolysis.
- Drug-bound CYPA complexes modulated RAS switch II motif residues, facilitating GTP hydrolysis in a mutation-specific manner.
- RAS mutants sensitive to GTPase activity stimulation showed greater susceptibility to treatment.
Conclusions:
- Pharmacological stimulation of GTP hydrolysis potentiates the therapeutic effects of tri-complex inhibitors for specific RAS mutants.
- This study establishes a foundation for developing therapeutics that inhibit cancer growth by enhancing mutant RAS GTPase activity.
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