Related Experiment Video

Updated: Jan 18, 2026

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
07:49

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

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RRAS and RRAS2 Mutations Are Recurrent Oncogenic Drivers in Lung Cancer and Are Sensitive to the Pan-RAS Inhibitor

Alexander J Pfeil1,2,3, Tom Zhang1,3,4, Ryan Cheng1,3

  • 1Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|January 16, 2026
PubMed
Abstract

Insights

New research identifies RRAS and RRAS2 mutations as oncogenic drivers in lung cancer. These mutations are potentially targetable with pan-RAS inhibitors like RMC-6236, offering new avenues for precision oncology.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • RRAS and RRAS2 are RAS-like GTPases similar to KRAS, HRAS, and NRAS.
  • Their role as oncogenic drivers in lung cancer is not well understood.

Purpose of the Study:

  • To investigate the prevalence and oncogenic potential of RRAS/RRAS2 mutations in non-small cell lung cancer (NSCLC).
  • To evaluate the efficacy of the pan-RAS inhibitor RMC-6236 against RRAS/RRAS2-mutant NSCLC.

Main Methods:

  • Comprehensive targeted DNA sequencing of 8,488 NSCLCs.
  • In vitro and in vivo modeling of RRASQ87L and RRAS2Q72L mutations in cell lines.
  • Assessment of signaling pathways (MAPK, PI3K-mTOR) and drug sensitivity (RMC-6236).

Main Results:

  • RRASQ87L/RRAS2Q72L mutations were found in ~0.45% of NSCLCs, often without other MAPK drivers.
  • These mutations activated MAPK and PI3K-mTOR signaling and transformed cells.
  • RMC-6236 inhibited proliferation, reduced ERK phosphorylation, induced apoptosis, and suppressed tumor growth in vivo.

Conclusions:

  • RRASQ87L and RRAS2Q72L mutations are recurrent, oncogenic drivers in NSCLC.
  • These findings support including RRAS/RRAS2 in molecular diagnostics for precision oncology.
  • Preclinical data support investigating pan-RAS inhibitors for RRAS/RRAS2-mutant lung cancers.

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