Targeting AKT for cancer therapy

Abstract

Targeted therapies in cancer aim to inhibit specific molecular targets responsible for enhanced tumor growth. AKT/PKB (protein kinase B) is a serine threonine kinase involved in several critical cellular pathways including survival, proliferation, invasion, apoptosis, and angiogenesis. Although phosphatidylinositol-3 kinase (PI3K) is the key regulator of AKT activation, numerous stimuli and kinases initiate pro-proliferative AKT signaling which results in the activation of AKT pathway to drive cellular growth and survival. Activating mutations and amplification of components of the AKT pathway are implicated in the pathogenesis of many cancers including breast and ovarian. Given its importance, AKT, it has been validated as a promising therapeutic target. This article summarizes AKT’s biological function and different classes of AKT inhibitors as anticancer agents. We also explore the efficacy of AKT inhibitors as monotherapies and in combination with cytotoxic and other targeted therapies. The complex mechanism following AKT inhibition, requires the addition of other therapies to prevent resistance and improve clinical response Further studies are necessary to determine additional rational combinations that can enhance efficacy of AKT inhibitors, potentially by targeting compensatory mechanisms, and/or enhancing apoptosis. The identification of biomarkers of response is essential for the development of successful therapeutics.