PI3K and AKT: Unfaithful Partners in Cancer

Abstract

The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway regulates multiple cellular processes. An overactivation of the pathway is frequently present in human malignancies and plays a key role in cancer progression. Hence, its inhibition has become a promising approach in cancer therapy. However, the development of resistances, such as the abrogation of negative feedback mechanisms or the activation of other proliferative signaling pathways, has considerably limited the anticancer efficacy of PI3K/AKT inhibitors. In addition, emerging evidence points out that although AKT is acknowledged as the major downstream effector of PI3K, both PI3K and AKT can operate independently of each other in cancer, revealing another level of complexity in this pathway. Here, we highlight the complex relationship between PI3K and AKT in cancer and further discuss the consequences of this relationship for cancer therapy.

Keywords: AKT; PI3K; cancer; signaling; therapies.

Figure 1

PI3K/AKT signaling pathway. Following its activation by tyrosine kinase receptors, PI3K catalyzes the phosphorylation of PtdIns(4,5)P₂ (phosphatidylinositol 4,5-bisphosphate) to PtdIns(3,4,5)P₃ (phosphatidylinositol 3,4,5-trisphosphate), resulting in the recruitment of PDK1 and AKT to the plasma membrane and their activation. AKT then acts upon multiple downstream effectors, leading to cell growth, proliferation and survival.

Figure 2

AKT-independent PI3K signaling in cancer. Several AKT-independent mechanisms used by PI3K to promote cancer growth have been described. They include activation of RAC, BTK in B cell malignancies, PDK1/SGK3 and mTORC2/NF-κB; mTORC2/c-Myc. Light gray ovals imply components of the signaling pathway that are not activated or bypassed.

Figure 3

Negative feedback loops in the PI3K/AKT pathway.

Figure 4

PI3K-independent AKT activation in cancer. Several kinases including Ack I, IKKε, TBK1, Src, PTK6 (protein tyrosine kinase 6) can activate AKT independently of PDK1 and mTORC2. Light gray ovals imply components of the signaling pathway that are not activated or bypassed.