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

• DOI: 10.1016/j.celrep.2022.111972
• Publication Date: 2023-01-14T16:53:23Z
• 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
• Keywords: Trametinib; Puma

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