Oncogenic mutant KRAS inhibition through oxidation at cysteine 118

Oncogenic mutant KRAS inhibition through oxidation at cysteine 118

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 KR...

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Main Authors: 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
Format: Article
Language:English
Published: Wiley 2025-02-01
Series:Molecular Oncology
Subjects:
cysteine modification
KRAS C118
NSCLC
oncogene
redox regulation
ROS
Online Access:https://doi.org/10.1002/1878-0261.13798
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Summary: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.
ISSN:1574-7891
1878-0261

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