The Akt signaling pathway: an emerging therapeutic target in malignant melanoma

Abstract

Studies using cultured melanoma cells and patient tumor biopsies have demonstrated deregulated PI3 kinase-Akt3 pathway activity in ~70% of melanomas. Furthermore, targeting Akt3 and downstream PRAS40 has been shown to inhibit melanoma tumor development in mice. Although these preclinical studies and several other reports using small interfering RNAs and pharmacological agents targeting key members of this pathway have been shown to retard melanoma development, analysis of early Phase I and Phase II clinical trials using pharmacological agents to target this pathway demonstrate the need for (1) selection of patients whose tumors have PI3 kinase-Akt pathway deregulation, (2) further optimization of therapeutic agents for increased potency and reduced toxicity, (3) the identification of additional targets in the same pathway or in other signaling cascades that synergistically inhibit the growth and progression of melanoma, and (4) better methods for targeted delivery of pharmaceutical agents inhibiting this pathway. In this review we discuss key potential targets in PI3K-Akt3 signaling, the status of pharmacological agents targeting these proteins, drugs under clinical development, and strategies to improve the efficacy of therapeutic agents targeting this pathway.

Figure 1

Schematic representation of key therapeutic targets in the PI3K/Akt and MAPK pathways together with pharmacological agents inhibiting members of these signaling cascades. Shown are the key therapeutic targets regulating melanoma development. Whereas PI3K/Akt3 pathway involved in cell survival and apoptosis regulation, MAPK pathway is implicated in cell proliferation. Targeting members of these signaling cascades using pharmacological agents has been shown to inhibit melanoma tumor development. Pharmacological agents inhibiting PI3K/Akt signaling; perifosine, 17-AAG, CCI-779 and RAD-001 have been evaluated in clinical trials. Vemurafenib and sorafenib targeting MAPK are also being evaluated in various clinical trials for inhibiting melanomas.

Figure 2

Mechanisms regulating PI3K pathway in melanoma. PI3K is one of the key proteins involved in the development of melanoma. PI3K expression and activities are regulated by mutational activation, elevated protein expression and loss of negative regulators such as PTEN. Activated PI3K converts PIP2s in to PIP3s, which in turn binds to plextrin homology domains of various kinases such as Akt thereby helps in the translocation of these proteins to cell membranes.