Targeting KRAS-mutant stomach/colorectal tumors by disrupting the ERK2-p53 complex
Xiang Wang, Qing Xie, Yanhui Ma, Jiaxin Yang, Jiayan Shen, Fangfei Peng, Yongfeng Zhang, Feng Jiang, Xiangyin Kong, Wenzhe Ma, Dandan Liu, Leizhen Zheng, Chen Qing, Jing‐Yu Lang
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.