Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery

Abstract

Evolving studies with several different targeted therapeutic agents are demonstrating that patients with genomic alterations of the target, including amplification, translocation and mutation, are more likely to respond to the therapy. Recent studies indicate that numerous components of the phosphatidylinositol-3-kinase (PI3K)/AKT pathway are targeted by amplification, mutation and translocation more frequently than any other pathway in cancer patients, with resultant activation of the pathway. This warrants exploiting the PI3K/AKT pathway for cancer drug discovery.

Loss of PI3K blocks cell-cycle progression in a Drosophila tumor model

“…Preclinical and clinical trials focus mainly on tumors that carry mutations in PI3K pathway components or that display abnormal levels of the biomarkers pAKT and PS6k1 (Hennessy et al, 2005;Cleary and Shapiro, 2010;Courtney et al, 2010). Our results are, however, an example for a case where tumors with no genetic alterations in PI3K signaling components are also highly susceptible to reduction of PI3K levels.…”

“…Compounds that block PI3K pathway activity are known to be potent inhibitors of mammalian tumor growth and inhibitors that target PI3K, and other members of the pathway are currently being tested in clinical trials (Hennessy et al, 2005;Cleary and Shapiro, 2010;Courtney et al, 2010). Preclinical and clinical trials focus mainly on tumors that carry mutations in PI3K pathway components or that display abnormal levels of the biomarkers pAKT and PS6k1 (Hennessy et al, 2005;Cleary and Shapiro, 2010;Courtney et al, 2010).…”

Macrophage migration inhibitory factor (MIF) promotes cell survival by activation of the Akt pathway and role for CSN5/JAB1 in the control of autocrine MIF activity

“…PI3K/ Akt signaling thus plays a major role in oncogenesis and it is not surprising that deregulations of components within this pathway are targets for cancer treatment (Chang et al, 2003;Osaki et al, 2004;Hennessy et al, 2005).…”

The expression of phospho-AKT1 and phospho-MTOR is associated with a favorable prognosis independent of PTEN expression in intrahepatic cholangiocarcinomas

“…5 Activated AKT1 phosphorylates, activates, or inhibits many downstream targets to regulate various cellular functions, including cell metabolism, protein synthesis, cell survival, inhibition of apoptosis, and cell cycle progression. 5,6 The aberrant expression or deregulation of AKT1 has been observed in many different types of tumors, and it is thought to be an important step for tumorigenesis or disease progression in these tumors. [7][8][9] On the other hand, the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was first discovered as a tumor suppressor on human chromosome 10q23.…”