Explore PI3K/AKT/mTOR

Understanding the PI3K/AKT pathway

PI3K/AKT/mTOR image: The PI3K/AKT signaling pathway regulates cell survival, proliferation, metabolism, and growth

FOXO=Forkhead box O; GSK3=glycogen synthase kinase 3; mTORC=mammalian target of rapamycin complex; PDK1=phosphoinositide-dependent kinase-1; PI3K=phosphatidylinositol 3-kinase; PI4,5P2=phosphatidylinositol 4,5-bisphosphate; PIP3=phosphatidylinositol 3,4,5-trisphosphate; PTEN=phosphatase and tensin homolog; RTK=receptor tyrosine kinase.

A crucial pathway influencing diverse cellular functions 1

The PI3K/AKT signaling pathway is a key regulator of normal cellular processes involved in cell growth, proliferation, metabolism, motility, survival, and apoptosis. Aberrant activation of the PI3K/AKT pathway promotes the survival and proliferation of tumor cells in many human cancers. 1,2

Key molecules involved in this signaling pathway

Phosphatidylinositol 3-kinase (PI3K), AKT, a serine/threonine protein kinase also known as protein kinase B (PKB), and mammalian target of rapamycin (mTOR) are 3 major nodes in the pathway. They are typically activated by upstream signaling of tyrosine kinases and other receptor molecules such as hormones and mitogenic factors. 3

There are 3 classes of PI3Ks, with Class I being widely implicated in cancer. 4,5 Class I PI3Ks are activated by receptor tyrosine kinases (RTKs) or G protein–coupled receptors (GPCRs), and their primary role is to convert phosphatidylinositol 4,5-bisphosphate (PI4,5P2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3). AKT, the central node of the pathway, is activated following recruitment to the plasma membrane by PIP3. It acts downstream of PI3K to regulate cellular processes, including cell survival, proliferation, and growth. 5,6 mTOR is a key protein in the pathway that acts both upstream and downstream of AKT.7 mTOR is active in 2 different multiprotein complexes, target of rapamycin complex (TORC) 1 and TORC2, and it regulates the protein synthesis necessary for cell growth, proliferation, angiogenesis, and other cellular endpoints. 7,8

PI3K/AKT pathway and cancer

Aberrant PI3K/AKT activation promotes tumor progression and resistance to treatment 9,10

The PI3K/AKT signaling pathway regulates cell survival and proliferation.11 Aberrant activation of the pathway is commonly observed in many human cancers, including breast, lung, endometrial, and prostate. 6,9,10,12

Increased activity of this pathway is often associated with tumor progression and resistance to cancer therapies. 9,10 The activation of the PI3K/AKT pathway has been implicated in de novo and acquired treatment resistance to targeted therapies in multiple tumor types. 13

Chemotherapeutic agents can modulate activity of the PI3K/AKT pathway, which contributes to the development of acquired resistance. 2

Aberrant activation can result from molecular alterations of the pathway's key components.9 Alterations in PI3K, AKT, or mTOR can induce cell line transformation and tumor formation in transgenic mice.14 Preclinical knockout of PI3K blocked oncogenic transformation.4 Knockout or suppression of AKT or mTOR has inhibited tumor growth and invasiveness in animal models. 15,16

References

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  6. Myers AP, Cantley LC. Sci Transl Med. 2010;2:48ps45. PMID: 20826838
  7. Slomovitz BM, Coleman RL. Clin Cancer Res. 2012;18:5856-5864. PMID: 23082003
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  12. Liu H, Zhang L, Zhang X, Cui Z. Onco Targets Ther. 2017;10:2865-2871. PMID: 28652768
  13. LoRusso PM. J Clin Oncol. 2016;34:3803-3815. PMID: 27621407
  14. Rodon J, Dienstmann R, Serra V, Tabernero J. Nat Rev Clin Oncol. 2013;10:143-153. PMID: 23400000
  15. Cheng JQ, Lindsley CW, Cheng GZ, Yang H, Nicosia SV. Oncogene. 2005;24:7482-7492. PMID: 16288295
  16. Statz CM, Patterson SE, Mockus SM. Targ Oncol. 2017;12:47-59. PMID: 27503005