2. Academic Validation
  3. MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade

MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade

  • Sci Adv. 2021 Nov 12;7(46):eabi6439. doi: 10.1126/sciadv.abi6439.
Qinbo Cai 1 2,  Wolong Zhou 1 3,  Wei Wang 1,  Bingning Dong 1 4,  Dong Han 1,  Tao Shen 1,  Chad J Creighton 4 5,  David D Moore 1 6,  Feng Yang 1
Affiliations

Affiliations

  • 1 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
  • 2 Center of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
  • 3 Department of Thoracic Surgery, Xiangya Hospital of Central South University, Changsha 410008, China.
  • 4 Department of Medicine, Baylor College of Medicine, Houston, TX 77070, USA.
  • 5 Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
  • 6 Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
PMID: 34767444 DOI: 10.1126/sciadv.abi6439
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.

Figures
Products