MAPK6-AKT Signaling Promotes Tumor Growth and Resistance to mTOR Kinase Blockade

Authors

Qinbo Cai
Wolong Zhou
Wei Wang
Bingning Dong
Dong Han
Tao Shen
Chad J Creighton
David D Moore
Feng Yang

Publication Date

11-12-2021

Journal

Science Advances

DOI

10.1126/sciadv.abi6439

PMID

34767444

PMCID

PMC8589317

PubMedCentral® Posted Date

11-12-2021

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

yes

Abstract

Mitogen-activated protein kinase 6 (MAPK6) is an atypical MAPK. Its function in regulating cancer growth remains elusive. Here, we reported that MAPK6 directly activated AKT and induced oncogenic outcomes. MAPK6 interacted with AKT through its C34 region and the C-terminal tail and phosphorylated AKT at S473 independent of mTORC2, the major S473 kinase. mTOR kinase inhibitors have not made notable progress in the clinic. Our identified MAPK6-AKT axis may provide a major resistance pathway. Besides repressing growth, inhibiting MAPK6 sensitized cancer cells to mTOR kinase inhibitors. MAPK6 overexpression is associated with decreased overall survival and the survival of patients with lung adenocarcinoma, mesothelioma, uveal melanoma, and breast cancer. MAPK6 expression also correlated with AKT phosphorylation at S473 in human cancer tissues. We conclude that MAPK6 can promote cancer by activating AKT independent of mTORC2 and targeting MAPK6, either alone or in combination with mTOR blockade, may be effective in cancers.

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