mTOR, a downstream effector1

mTOR controls cell growth and proliferation as a downstream effector1-3

PI3K/AKT/mTOR image: Activation of mTORC1 effects cell growth and metabolism

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.

Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that plays an important role in the regulation of cell growth and proliferation by monitoring nutrient availability, cellular energy levels, oxygen levels, and mitogenic signals.2,3

mTOR exists in 2 distinct intracellular complexes, mammalian target of rapamycin complex (mTORC) 1 and mTORC2. mTORC1 is mainly involved in the regulation of ribosomal biogenesis and protein synthesis. Activation of mTORC1 is achieved through phosphatidylinositol 3-kinase (PI3K) and AKT, while the TSC1-TSC2 (also known as hamartin-tuberin) complex is responsible for mTORC1 inhibition. mTORC2 is activated upon stimulation by growth factors and leads to activation of AKT and protein kinase C-alpha. mTORC2 also controls the activity of GTPases (eg, Rac and Rho) involved in cellular migration, actin cytoskeleton regulation, and cell survival.1

Aberrant activation of the mTOR pathway has been implicated in a variety of cancers, including breast, lymphoma, and renal cell carcinoma.4

mTOR conditional knockout inhibited tumorigenesis in phosphatase and tensin homolog (PTEN)-deficient preclinical models.5 In addition, mTOR inhibitors demonstrated antitumor activity in endometrial cancer cell lines, with the greatest activity seen in cells with phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA) and/or PTEN mutations.6

References

  1. Pópulo H, Lopes JM, Soares P. Int J Mol Sci. 2012;13:1886-1918. PMID: 22408430
  2. Liu P, Cheng H, Roberts TM, Zhao JJ. Nat Rev Drug Discov. 2009;8:627-644. PMID: 19644473
  3. Zhou H, Huang S. Curr Protein Pept Sci. 2011;12:30-42. PMID: 21190521
  4. Advani SH. Indian J Med Paediatr Oncol. 2010;31:132-136. PMID: 21584218
  5. Statz CM, Patterson SE, Mockus SM. Targ Oncol. 2017;12:47-59. PMID: 27503005
  6. Slomovitz BM, Coleman RL. Clin Cancer Res. 2012;18:5856-5864. PMID: 23082003