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PI3K-independent AKT activation in cancers: a treasure trove for novel therapeutics

Kiran Mahajan1, Nupam P Mahajan

  • 1Drug Discovery Department, Moffitt Cancer Center, Tampa, Florida 33612, USA. kiran.mahajan@moffitt.org

Journal of Cellular Physiology
|February 7, 2012
PubMed

Insights

Dysregulated AKT signaling in cancer involves kinases beyond PI3K. Targeting these alternate AKT-activating kinases offers a strategy to overcome drug resistance in cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The AKT/PKB serine/threonine kinase is crucial for cell growth and survival, and its dysregulation is common in cancer.
  • Phosphatidylinositol-3-OH kinase (PI3K) is a known activator of AKT, but other kinases also play a role.

Purpose of the Study:

  • To explore the role of alternative tyrosine and serine/threonine kinases in activating AKT signaling.
  • To investigate the potential of targeting these alternate kinases for cancer therapy and overcoming drug resistance.

Main Methods:

  • Literature review of recent studies on AKT activation pathways.
  • Analysis of kinase involvement in cancer cell proliferation and survival.

Main Results:

  • Several tyrosine kinases (Ack1/TNK2, Src, PTK6) and serine/threonine kinases (TBK1, IKBKE, DNAPKcs) directly activate AKT.
  • These alternate kinases can be activated by growth factors, inflammatory, and genotoxic stimuli.
  • Aberrant activation of these kinases is linked to malignancy.

Conclusions:

  • Targeting alternate AKT-activating kinases represents a promising therapeutic strategy.
  • Inhibiting these kinases early in treatment may help overcome resistance to PI3K inhibitors in cancer patients.

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