Targeting protein kinase-b3 (akt3) signaling in melanoma

ABSTRACT

Introduction: Deregulated Akt activity leading to apoptosis inhibition, enhanced proliferation and drug resistance has been shown to be responsible for 35–70% of advanced metastatic melanomas. Of the three isoforms, the majority of melanomas have elevated Akt3 expression and activity. Hence, potent inhibitors targeting Akt are urgently required, which is possible only if (a) the factors responsible for the failure of Akt inhibitors in clinical trials is known; and (b) the information pertaining to synergistically acting targeted therapeutics is available.

Areas covered: This review provides a brief introduction of the PI3K-Akt signaling pathway and its role in melanoma development. In addition, the functional role of key Akt pathway members such as PRAS40, GSK3 kinases, WEE1 kinase in melanoma development are discussed together with strategies to modulate these targets. Efficacy and safety of Akt inhibitors is also discussed. Finally, the mechanism(s) through which Akt leads to drug resistance is discussed in this expert opinion review.

Expert opinion: Even though Akt play key roles in melanoma tumor progression, cell survival and drug resistance, many gaps still exist that require further understanding of Akt functions, especially in the (a) metastatic spread; (b) circulating melanoma cells survival; and (c) melanoma stem cells growth.

KEYWORDS:

• AKT3
• Akt inhibitors
• drug resistance
• melanoma
• PI3K
• PRAS40
• PTEN

Article highlights

• Emphasized are the key roles played by the Akt3 kinase and its down-stream targets in the growth and development of melanoma.

• The functional role played by downstream members of the Akt3 pathway such as PRAS40 and GSK3α in the regulation of melanoma cell apoptosis, proliferation, and angiogenesis are highlighted.

• The important role played by the Akt3 signaling cascade in the drug resistance is discussed.

• Recent approaches for treating malignant melanomas by targeting Akt to inhibit metastasis and improve responsiveness to pharmacological agent is overviewed.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was funded with research support from Foreman Foundation for Melanoma Research, Geltrude Foundation for Melanoma Research and Penn State Chocolate Tour Research Foundation.