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

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.

• Authors: 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
• Journal: Cell reports (Cell Rep) Vol. 42 Issue 1 Pg. 111972 (01 31 2023) ISSN: 2211-1247 [Electronic] United States
• PMID: 36641751 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

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

Topics

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