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

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	311-328
Number of pages	18
Journal	Molecular oncology
Volume	19
Issue number	2
DOIs	https://doi.org/10.1002/1878-0261.13798
State	Published - Feb 2025

Keywords

KRAS C118
NSCLC
ROS
cysteine modification
oncogene
redox regulation

ASJC Scopus subject areas

Molecular Medicine
Oncology
Genetics
Cancer Research

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title = "Oncogenic mutant KRAS inhibition through oxidation at cysteine 118",

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",

author = "Maximilian Kramer-Drauberg and Ettore Petrini and Alessia Mira and Enrico Patrucco and Rossella Scardaci and Ilenia Savinelli and Haiyun Wang and Keying Qiao and Giovanna Carr{\`a} and Nokin, {Marie Julie} and Zhiwei Zhou and Westover, {Kenneth D.} and David Santamaria and Porporato, {Paolo E.} and Chiara Ambrogio",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.",

year = "2025",

month = feb,

doi = "10.1002/1878-0261.13798",

language = "English (US)",

volume = "19",

pages = "311--328",

journal = "Molecular oncology",

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T1 - Oncogenic mutant KRAS inhibition through oxidation at cysteine 118

AU - Kramer-Drauberg, Maximilian

AU - Petrini, Ettore

AU - Mira, Alessia

AU - Patrucco, Enrico

AU - Scardaci, Rossella

AU - Savinelli, Ilenia

AU - Wang, Haiyun

AU - Qiao, Keying

AU - Carrà, Giovanna

AU - Nokin, Marie Julie

AU - Zhou, Zhiwei

AU - Westover, Kenneth D.

AU - Santamaria, David

AU - Porporato, Paolo E.

AU - Ambrogio, Chiara

PY - 2025/2

Y1 - 2025/2

N2 - 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.

AB - 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.

KW - KRAS C118

KW - NSCLC

KW - ROS

KW - cysteine modification

KW - oncogene

KW - redox regulation

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JO - Molecular oncology

JF - Molecular oncology

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ER -

Oncogenic mutant KRAS inhibition through oxidation at cysteine 118

Abstract

Keywords

ASJC Scopus subject areas

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