Related Experiment Video

Updated: Jun 1, 2025

Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein
07:08

Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein

Published on: January 16, 2020

5.6K

Oncogenic mutant KRAS inhibition through oxidation at cysteine 118

Maximilian Kramer-Drauberg1, Ettore Petrini1, Alessia Mira1

  • 1Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Italy.

Molecular Oncology
|January 22, 2025
PubMed

Insights

Specific reactive oxygen species activate Kirsten rat sarcoma virus (KRAS) GTPase. Researchers found that oxidizing KRAS at cysteine 118 selectively inhibits oncogenic mutant KRAS, suggesting new anti-cancer therapies.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Reactive oxygen species (ROS) activate GTPase Kirsten rat sarcoma virus (KRAS) via cysteine 118 (C118) oxidation.
  • This oxidation leads to guanosine diphosphate (GDP) release, modulating KRAS activity.

Purpose of the Study:

  • To investigate the selective inhibition of oncogenic mutant KRAS through C118 oxidation.
  • To explore the potential of oxidation-based therapeutic strategies against KRAS-driven cancers.

Main Methods:

  • Mimicking permanent C118 oxidation by creating a KRAS C118D mutant.
  • In vitro and in vivo experiments to assess the inhibition of mutant KRAS.
  • Utilizing a combination of paraquat (pro-oxidant) and N(ω)-nitro-l-arginine methyl ester (nitric oxide inhibitor) to induce C118 oxidation.

Main Results:

  • The KRAS C118D mutant demonstrated selective inhibition of oncogenic mutant KRAS.
  • Combined treatment with paraquat and the nitric oxide inhibitor effectively inhibited mutant KRAS activity via C118 oxidation.
  • Confirmed the vulnerability of human mutant KRAS to oxidative stress.

Conclusions:

  • Human mutant KRAS is selectively inhibited by oxidation at C118.
  • Oxidation-based strategies targeting C118 present a promising avenue for developing novel anti-KRAS cancer therapies.
Keywords:
KRAS C118NSCLCROScysteine modificationoncogeneredox regulation

More Related Videos

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

17.8K
Resin-Assisted Capture Coupled with Isobaric Tandem Mass Tag Labeling for Multiplexed Quantification of Protein Thiol Oxidation07:16

Resin-Assisted Capture Coupled with Isobaric Tandem Mass Tag Labeling for Multiplexed Quantification of Protein Thiol Oxidation

Published on: June 21, 2021

1.7K

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...
6.1K
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...
3.7K
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...
8.7K
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...
4.4K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
3.4K
Electron Transport Chain: Complex I and II01:46

Electron Transport Chain: Complex I and II

The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.
ROS generation is regulated and maintained at moderate levels necessary...
10.7K