Oncogenic mutant KRAS inhibition through oxidation at cysteine 118

Maximilian Kramer-Drauberg; Ettore Petrini; Alessia Mira; Enrico Patrucco; Rossella Scardaci; Ilenia Savinelli; Haiyun Wang; Keying Qiao; Giovanna Carrà; Marie-Julie Nokin; Zhiwei Zhou; Kenneth D Westover; David Santamaria; Paolo E Porporato; Chiara Ambrogio

doi:10.1002/1878-0261.13798

Oncogenic mutant KRAS inhibition through oxidation at cysteine 118

Mol Oncol. 2025 Jan 21. doi: 10.1002/1878-0261.13798. Online ahead of print.

Authors

Maximilian Kramer-Drauberg¹, Ettore Petrini¹, Alessia Mira¹, Enrico Patrucco¹, Rossella Scardaci¹, Ilenia Savinelli¹, Haiyun Wang², Keying Qiao², Giovanna Carrà³, Marie-Julie Nokin⁴, Zhiwei Zhou^{5

6}, Kenneth D Westover^{5

6}, David Santamaria⁷, Paolo E Porporato¹, Chiara Ambrogio¹

Affiliations

¹ Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Italy.
² School of Life Sciences and Technology, Tongji University, Shanghai, China.
³ Department of Clinical and Biological Sciences, University of Torino, Orbassano, Italy.
⁴ Laboratory of Tumor and Development Biology, GIGA-Cancer, University of Liege, Belgium.
⁵ Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁶ Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁷ Molecular Mechanisms of Cancer Program, Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Spain.

PMID: 39838816
DOI: 10.1002/1878-0261.13798

Abstract

Specific reactive oxygen species activate the GTPase Kirsten rat sarcoma virus (KRAS) by reacting with cysteine 118 (C118), leading to an electron transfer between C118 and nucleoside guanosine diphosphate (GDP), which causes the release of GDP. Here, we have mimicked permanent oxidation of human KRAS at C118 by replacing C118 with aspartic acid (C118D) in KRAS to show that oncogenic mutant KRAS is selectively inhibited via oxidation at C118, both in vitro and in vivo. Moreover, the combined treatment of hydrogen-peroxide-producing pro-oxidant paraquat and nitric-oxide-producing inhibitor N(ω)-nitro-l-arginine methyl ester selectively inhibits human mutant KRAS activity by inducing oxidization at C118. Our study shows for the first time the vulnerability of human mutant KRAS to oxidation, thereby paving the way to explore oxidation-based anti-KRAS treatments in humans.

Keywords: KRAS C118; NSCLC; ROS; cysteine modification; oncogene; redox regulation.

Abstract

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