Related Experiment Video

Updated: Jun 9, 2025

Detection of Small GTPase Prenylation and GTP Binding Using Membrane Fractionation and GTPase-linked Immunosorbent Assay
13:51

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
PubMed

Insights

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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