Targeting the PI3-kinase/Akt/mTOR signaling pathway

Abstract

This article presents an overview of the PI3K/Akt/mTOR signaling pathway. As a central regulator of cell growth, protein translation, survival, and metabolism, activation of this signaling pathway contributes to the pathogenesis of many tumor types. Biochemical and genetic aberrations of this pathway observed in various cancer types are explored. Last, pathway inhibitors both in development and already approved by the Food and Drug Administration are discussed.

Keywords: Cell signaling; Molecular targeted therapy; PI3K/Akt/mTOR signaling pathway; PTEN.

Figure 1

Growth factors, insulin, nutrients and energy status regulate the activation of the PI3K/Akt/mTOR signaling network. Protein synthesis, cell growth and proliferation, and metabolic functions are regulated by downstream effectors of the pathway, such as 4E-BP1 and S6K. Boxes indicate therapies targeting the pathway. Arrows represent activation and bars represent inhibition. Abbreviations: 4E-BP1, eukaryotic translation initiation factor 4E-binding protein 1; AMPK, adenosine monophosphate-activated protein kinase; ASK1, apoptosis signalregulating kinase 1; ATP, adenosine-5’-triphosphate; BAD, BCL2-associated agonist of cell death; FKBP-12, FK506-binding protein, 12 kD; FoxO, forkhead box O; GDP, guanosine diphosphate; GSK3, glycogen synthase kinase 3; GTP, guanosine-5’-triphosphate; IRS1, insulin receptor substrate 1; MAP4K3, mitogen-activated protein kinase kinase kinase kinase 3; mLST8, mTOR associated protein, LST8 homolog; mTOR, mammalian target of rapamycin; mTORC1, mTOR complex 1; mTORC2, mTOR complex 2; PDK-1, phosphoinositide-dependent kinase 1; PI3K, phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol (4,5) biphosphate; PIP3, phosphatidylinositol (3,4,5) triphosphate; PRAS40, proline-rich Akt1 substrate 40; PTEN, phosphatase and tensin homolog deleted from chromosome 10; Rheb, Ras homolog enriched in brain; RTK, receptor tyrosine kinase; S6K, ribosomal protein S6 kinase; SIN1, stress-activated mitogen-activated protein kinase associated protein 1; TSC1, tuberous sclerosis complex 1; TSC2, tuberous sclerosis complex 2.