A kinase-independent function of AKT promotes cancer cell survival

Area of Science:

• Molecular Biology
• Cancer Research
• Drug Development

Background:

• The serine-threonine kinase AKT is a key regulator of cell proliferation and survival through protein phosphorylation.
• Its known function is primarily enzymatic, involving the regulation of downstream substrates.

Purpose of the Study:

• To investigate and characterize a potential kinase-independent function of AKT.
• To explore the implications of this non-enzymatic function in cancer cells and its impact on therapeutic strategies.

Main Methods:

• Utilized catalytically inactive AKT mutants (K179M and G161V) to study kinase-independent functions.
• Assessed AKT function in cancer cells with specific genetic alterations (MET, HER2, PI3K) and in primary human melanocytes.
• Evaluated the efficacy of ATP-competitive and allosteric AKT inhibitors against both enzymatic and non-enzymatic AKT functions.

Main Results:

• Catalytically inactive AKT (K179M) conferred protection against drug-induced cell death in cancer cells, dependent on its PH-domain.
• A melanoma-derived AKT mutant (G161V), lacking in vitro kinase activity, promoted growth factor-independent survival of melanocytes.
• ATP-competitive AKT inhibitors were ineffective against the kinase-independent function of AKT.

Conclusions:

• AKT possesses a significant kinase-independent function that contributes to cancer cell survival and drug resistance.
• This non-enzymatic activity is crucial for understanding AKT's role in cancer.
• The findings highlight limitations of current ATP-competitive AKT inhibitors and suggest allosteric inhibitors may be more effective for targeting AKT in cancer therapy.