Targeting PI3K/Akt signal transduction for cancer therapy

Abstract

The phosphatidylinositol 3-kinase (PI3K)/Akt pathway plays a crucial role in various cellular processes and is aberrantly activated in cancers, contributing to the occurrence and progression of tumors. Examining the upstream and downstream nodes of this pathway could allow full elucidation of its function. Based on accumulating evidence, strategies targeting major components of the pathway might provide new insights for cancer drug discovery. Researchers have explored the use of some inhibitors targeting this pathway to block survival pathways. However, because oncogenic PI3K pathway activation occurs through various mechanisms, the clinical efficacies of these inhibitors are limited. Moreover, pathway activation is accompanied by the development of therapeutic resistance. Therefore, strategies involving pathway inhibitors and other cancer treatments in combination might solve the therapeutic dilemma. In this review, we discuss the roles of the PI3K/Akt pathway in various cancer phenotypes, review the current statuses of different PI3K/Akt inhibitors, and introduce combination therapies consisting of signaling inhibitors and conventional cancer therapies. The information presented herein suggests that cascading inhibitors of the PI3K/Akt signaling pathway, either alone or in combination with other therapies, are the most effective treatment strategy for cancer.

Fig. 1

Upstream activation of the PI3K/Akt signaling pathway. On the one hand, ligands combined with specific RTKs (EGFR, VEGFR and FGFR) can activate class I PI3Ks via RAS; on the other hand, class I PI3Ks can be activated by BCRs through B cell adapters and by GPCRs. The FGFR substrate FRS2 is phosphorylated in combination with GRB2, SOS and GAB1 to activate class I PI3Ks. In addition to being activated by EGFR, class II PI3Ks can be activated by TCRs. While class III PI3Ks are activated by amino acids, total activated PI3K phosphorylates the third carbon of the PIP2 inositol head and transforms it into PIP3 to thereby activate AKT via PDK1 and RAC, and this transformation process can be inhibited by PTEN. In addition, IGF-1 in combination with IGF1R can recruit IRS-1 and class I PI3Ks and then participate in the conversion of PIP2 to PIP3. Moreover, mTORC2 can affect the activity of Akt by affecting the phosphorylation of Akt and then affect downstream mTORC1 via TSC1/2, and both Akt and mTORC1 can be activated by TBK1. Moreover, TRAF6 can affect the activity of Akt by affecting its ubiquitylation. Furthermore, DNA damage can affect Akt via ATM and ATR

Fig. 2

Downstream effectors of the PI3K/Akt signaling pathway and their cellular functions. The activation of Akt signaling can promote (arrows) or inhibit (blocking arrows) the phosphorylation of downstream effectors. Downstream regulation by Akt contributes to many cellular processes, including tumor growth, tumor survival, tumor cell proliferation, cancer immunity, cancer metabolism and cancer angiogenesis

Fig. 3

PI3K/Akt signaling and cancer. Various biological processes are regulated by the PI3K/Akt pathway via key mediators/pathways