Targeting the phosphatidylinositol 3-kinase signaling pathway in breast cancer

Abstract

The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) network plays a key regulatory function in cell survival, proliferation, migration, metabolism, angiogenesis, and apoptosis. Genetic aberrations found at different levels, either with activation of oncogenes or inactivation of tumor suppressors, make this pathway one of the most commonly disrupted in human breast cancer. The PI3K-dependent phosphorylation and activation of the serine/threonine kinase AKT is a key activator of cell survival mechanisms. The activation of the oncogene PIK3CA and the loss of regulators of AKT including the tumor suppressor gene PTEN are mutations commonly found in breast tumors. AKT relieves the negative regulation of mTOR to activate protein synthesis and cell proliferation through S6K and 4EBP1. The common activation of the PI3K pathway in breast cancer has led to the development of compounds targeting the effector mechanisms of the pathway including selective and pan-PI3K/pan-AKT inhibitors, rapamycin analogs for mTOR inhibition, and TOR-catalytic subunit inhibitors. The influences of other oncogenic pathways such as Ras-Raf-Mek on the PI3K pathway and the known feedback mechanisms of activation have prompted the use of compounds with broader effect at multiple levels and rational combination strategies to obtain a more potent antitumor activity and possibly a meaningful clinical effect. Here, we review the biology of the network, its role in the development and progression of breast cancer, and the evaluation of targeted therapies in clinical trials.

Figure 1.

The PI3K/AKT/mTOR signaling network regulates cell survival, proliferation, migration, metabolism, and apoptosis, integrating the growth factor signaling pathway, nutrient status, and other oncogenic pathways. Aberrations at different levels of the network are implicated in breast cancer development and progression. Different therapies targeting the pathway are being developed and included in clinical trials. Arrows represent activation; bars represent inhibition. Abbreviations: 4EBP1, 4E-binding protein 1; AMPK, adenosine monophosphate-activated protein kinase; Bad, BCL2-associated agonist of cell death; FOXO, forkhead box O1; GPCR, G protein-coupled receptor; GSK3, glycogen synthase kinase 3; IRS1, insulin receptor substrate 1; mLST8, mTOR associated protein, LST8 homolog; mTOR, mammalian target of rapamycin; mTORC1, mTOR complex 1; mTORC2, mTOR complex 2; PI3K, phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol (4,5) biphosphate; PIP3, phosphatidylinositol (3,4,5) triphosphate; PRAS40, proline-rich Akt substrate 40; PTEN, phosphatase and tensin homolog; Rheb, Ras homolog enriched in brain; S6K, ribosomal protein S6 kinase; TKR, tyrosine kinase receptors; TSC1, tuberous sclerosis complex 1; TSC2, tuberous sclerosis complex 2.