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

Qinbo Cai1,2, Wolong Zhou1,3, Wei Wang1

  • 1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.

Science Advances
|November 12, 2021
PubMed

Insights

Mitogen-activated protein kinase 6 (MAPK6) activates AKT, promoting cancer growth. Inhibiting MAPK6 may overcome resistance to mTOR kinase inhibitors, offering new therapeutic strategies for various cancers.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • Mitogen-activated protein kinase 6 (MAPK6) is an atypical MAPK.
  • The role of MAPK6 in cancer progression is largely unknown.

Purpose of the Study:

  • To investigate the function of MAPK6 in cancer growth.
  • To elucidate the molecular mechanisms by which MAPK6 influences cancer progression.

Main Methods:

  • Investigated the interaction between MAPK6 and AKT.
  • Assessed the phosphorylation of AKT at S473 by MAPK6.
  • Examined the effect of MAPK6 inhibition on cancer cell sensitivity to mTOR kinase inhibitors.
  • Correlated MAPK6 expression with patient survival and AKT phosphorylation in human cancer tissues.

Main Results:

  • MAPK6 directly activates AKT, leading to oncogenic outcomes.
  • MAPK6 phosphorylates AKT at S473 independently of mTORC2.
  • MAPK6 overexpression is linked to decreased survival in lung adenocarcinoma, mesothelioma, uveal melanoma, and breast cancer.
  • MAPK6 expression correlates with AKT phosphorylation at S473 in human cancers.

Conclusions:

  • MAPK6 promotes cancer by activating AKT independent of mTORC2.
  • The MAPK6-AKT axis represents a potential resistance pathway to mTOR kinase inhibitors.
  • Targeting MAPK6, alone or with mTOR blockade, could be an effective cancer therapy.

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