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

doi:10.1016/j.celrep.2022.111972

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

Cell Rep. 2023 Jan 31;42(1):111972. doi: 10.1016/j.celrep.2022.111972. Epub 2023 Jan 14.

Authors

Xiang Wang¹, Qing Xie¹, Yan Ji², Jiaxin Yang¹, Jiayan Shen¹, Fangfei Peng¹, Yongfeng Zhang¹, Feng Jiang³, Xiangyin Kong¹, Wenzhe Ma⁴, Dandan Liu⁵, Leizhen Zheng⁶, Chen Qing⁵, Jing-Yu Lang⁷

Affiliations

¹ 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.
² 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.
³ Department of Radiation Oncology, The Cancer Hospital of University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou 310022, P.R. China.
⁴ State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, P.R. China.
⁵ School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, P.R. China.
⁶ Department of Oncology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, P.R. China.
⁷ 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. Electronic address: jylang@sibs.ac.cn.

PMID: 36641751
DOI: 10.1016/j.celrep.2022.111972

Abstract

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.

Keywords: CP: Cancer; ERK2; KRAS; p53; stomach/colorectal cancer; trametinib.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Colorectal Neoplasms* / genetics
Colorectal Neoplasms* / metabolism
Humans
Phosphorylation
Proto-Oncogene Proteins p21(ras)* / genetics
Proto-Oncogene Proteins p21(ras)* / metabolism
Stomach
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism

Substances

Proto-Oncogene Proteins p21(ras)
Tumor Suppressor Protein p53
KRAS protein, human