Related Experiment Video

Updated: Jun 23, 2026

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans
08:12

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans

Published on: October 5, 2020

Selective Inhibition of KRASG13C Reveals an Increased Dependence on Wild-Type RAS Isoforms in Codon 13 RAS-Mutant

Kyle J Seamon1, Yongxian Zhuang2, Yu Chi Yang1

  • 1Revolution Medicines (United States) Redwood City, CA United States.

Cancer Discovery
|June 22, 2026
PubMed

Insights

New covalent KRAS G13C inhibitors show promise for treating cancers. Combining RMC-8839 with other inhibitors may overcome resistance by targeting wild-type RAS(ON) signaling in KRAS G13C-mutant tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Covalent KRAS G12C inhibitors have advanced cancer therapy, but targeted treatments for many RAS-mutant cancers remain limited.
  • KRAS G13C mutations represent a distinct subset of RAS alterations lacking specific targeted therapies.

Purpose of the Study:

  • To investigate RMC-8839, a novel covalent inhibitor targeting RAS(ON) G13C.
  • To explore the mechanisms of resistance to KRAS G13C inhibitors, including the role of wild-type RAS(ON).

Main Methods:

  • In vitro studies using KRAS G13C-mutant cancer cell lines.
  • Xenograft models of KRAS G13C-mutant cancers.
  • Biochemical analysis of KRAS G13C protein stability and nucleotide exchange.
  • Combination therapy studies with RMC-8839 and a multi-selective RAS(ON) inhibitor.

Main Results:

  • RMC-8839 demonstrated tumor regressions in KRAS G13C-mutant xenografts.
  • Incomplete RAS pathway suppression was observed in some cell lines, indicating potential resistance mechanisms.
  • KRAS G13C mutations exhibit unique biochemical properties including decreased stability and altered nucleotide exchange.
  • Co-occurring mutations enhancing wild-type RAS activation were found in codon 13 mutant tumors.
  • Combination therapy significantly enhanced tumor growth inhibition compared to single-agent treatment.

Conclusions:

  • RMC-8839 is a potent inhibitor of KRAS G13C.
  • Wild-type RAS(ON) signaling contributes to resistance in KRAS G13C-mutant cancers.
  • Combination strategies targeting both mutant and wild-type RAS are crucial for effective treatment of KRAS G13C-mutant cancers.

More Related Videos

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods07:49

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

Published on: July 17, 2019

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer06:51

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer

Published on: July 21, 2018

Related Concept Videos

The Ras Gene02:38

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...
Small GTPases - Ras and Rho01:24

Small GTPases - Ras and Rho

Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
Cancer-Critical Genes I: Proto-oncogenes01:33

Cancer-Critical Genes I: Proto-oncogenes

Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
The Ras Gene02:38

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...