Deregulation of the Akt Pathway in Human Cancer

Abstract

Akt (protein kinase B) is a serine/threonine kinase which is a central regulator of widely divergent cellular processes including proliferation, differentiation, migration, survival and metabolism. Akt is activated by a variety of stimuli, through growth factor receptors, in phosphatidylinositol 3-kinase (PI3K)-dependent manner. Akt is also negatively regulated by the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN). A disruption of normal Akt/PKB/PTEN signaling frequently occurs in many human cancers, which plays an important role in cancer development, progression and therapeutic resistance. Numerous studies have revealed the blockage of Akt signaling to result in apoptosis and growth inhibition of tumor cells. Therefore, this signaling pathway, including both upstream and downstream of Akt, has recently attracted considerable attention as a new target for effective cancer therapeutic strategies. In fact, many inhibitors of Akt pathway have been identified and clinical studies of some agents are ongoing. In this review, we describe Akt signaling pathway components and its cellular functions as well as the alterations in human cancers and the therapeutic approaches for targeting the Akt pathway in cancer.

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

“…Constitutive pathway activation can result from the distinct and/or complementary biological events including (i) constitutively active mutants or amplification of receptor tyrosine kinases (for example, epidermal growth factor receptor or ErbB2) leading to constitutive recruitment and activation of PI3K and downstream effectors; (ii) amplification of PI3K; (iii) presence of activating mutations in the PIK3CA gene encoding the p110a catalytic subunit; (iv) overexpression of the downstream kinase Akt; (v) loss or inactivating mutations of the tumor suppressor gene PTEN, an endogenous negative regulator of the PI3K pathway or (vi) constitutive recruitment and activation by mutant forms of the Ras oncogene (Carnero et al, 2008;Tokunaga et al, 2008;Maira et al, 2008b). The preceding alterations trigger a cascade of biological events, from cell growth and proliferation to survival and migration, which drive tumor progression.…”

DNA Repair, Cancer and Cancer Therapy

“…There has been a tremendous interest in developing novel drugs against this pathway. Many small-molecule inhibitors against PI-3K, AKT, and mTOR have been developed and tested in tumor cells (Carnero et al,2008;Fasolo & Sessa, 2008;Franke, 2008;LoPiccolo et al, 2008;Marone et al, 2008;Nakamura et al, 2005;Steelman et al, 2008;Tokunaga et al, 2008;Yap et al, 2008). One unique feature of targeting this pathway is to target the apoptosis-protecting role of AKT without negating its HR-suppressing function (Plo et al, 2008).…”

Induction of death receptor 5 expression in tumor vasculature by perifosine restores the vascular disruption activity of TRAIL-expressing CD34+ cells

“…PI3K/Akt signaling pathway represents an attractive target for anticancer therapy [1][2][3][4][5]. Many new agents targeting this pathway are currently being developed [6].…”