Targeting KRAS-mutant stomach/colorectal tumors by disrupting the ERK2-p53 complex

Xiang Wang; Qing Xie; Yan Ji; Jiaxin Yang; Jiayan Shen; Fangfei Peng; Yongfeng Zhang; Feng Jiang; Xiangyin Kong; Wenzhe Ma; Dandan Liu; Leizhen Zheng; Chen Qing; Jing-Yu Lang

Cell Reports (Jan 2023)

Targeting KRAS-mutant stomach/colorectal tumors by disrupting the ERK2-p53 complex

Xiang Wang,
Qing Xie,
Yan Ji,
Jiaxin Yang,
Jiayan Shen,
Fangfei Peng,
Yongfeng Zhang,
Feng Jiang,
Xiangyin Kong,
Wenzhe Ma,
Dandan Liu,
Leizhen Zheng,
Chen Qing,
Jing-Yu Lang

Affiliations

Xiang Wang: The CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, P.R. China
Qing Xie: The CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, P.R. China
Yan Ji: Bioinformatics Core, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, P.R. China
Jiaxin Yang: The CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, P.R. China
Jiayan Shen: The CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, P.R. China
Fangfei Peng: The CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, P.R. China
Yongfeng Zhang: The CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, P.R. China
Feng Jiang: Department of Radiation Oncology, The Cancer Hospital of University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou 310022, P.R. China
Xiangyin Kong: The CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, P.R. China
Wenzhe Ma: State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, P.R. China
Dandan Liu: School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, P.R. China
Leizhen Zheng: Department of Oncology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, P.R. China
Chen Qing: School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, P.R. China
Jing-Yu Lang: The CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, P.R. China; Corresponding author

Journal volume & issue: Vol. 42, no. 1
p. 111972

Abstract

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Summary: KRAS is widely mutated in human cancers, resulting in unchecked tumor proliferation and metastasis, which makes identifying KRAS-targeting therapies a priority. Herein, we observe that mutant KRAS specifically promotes the formation of the ERK2-p53 complex in stomach/colorectal tumor cells. Disruption of this complex by applying MEK1/2 and ERK2 inhibitors elicits strong apoptotic responses in a p53-dependent manner, validated by genome-wide knockout screening. Mechanistically, p53 physically associates with phosphorylated ERK2 through a hydrophobic interaction in the presence of mutant KRAS, which suppresses p53 activation by preventing the recruitment of p300/CBP; trametinib disrupts the ERK2-p53 complex by reducing ERK2 phosphorylation, allowing the acetylation of p53 protein by recruiting p300/CBP; acetylated p53 activates PUMA transcription and thereby kills KRAS-mutant tumors. Our study shows an important role for the ERK2-p53 complex and provides a potential therapeutic strategy for treating KRAS-mutant cancer.

CP: Cancer

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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