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bioRxiv · 10.1101/2020.08.12.247460

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

Lang, J.-Y.·Wang, X.·Xie, Q.·Ji, Y.·Shen, J.·Wang, C.·Jiang, X.·Chen, Z.·Zhang, Y.·Kong, X.·Ding, J.
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Abstract

KRAS is widely mutated in human cancers, resulting in nearly unchecked tumour proliferation and metastasis. No therapies have been developed for targeting KRAS-mutant tumours. Herein, we observed that mutant KRAS specifically promoted the formation of ERK2-p53 complex in stomach/colorectal tumour 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 the 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 tumours. Our study unveils an important role of the ERK2-p53 complex and provides a potential therapeutic strategy for treating KRAS-mutant cancer via ERK2 inhibition.

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Lang, J.-Y., Wang, X., Xie, Q., Ji, Y., Shen, J., Wang, C., Jiang, X., Chen, Z., Zhang, Y., Kong, X., Ding, J.. 2020-08-12. Targeting KRAS-mutant stomach/colorectal tumours by disrupting the ERK2-p53 complex. https://doi.org/10.1101/2020.08.12.247460

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