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AKT

Reference work entry

Abstract

AKT, also known as protein kinase B and RAC-PK, was first discovered as an oncogene transduced by the acute transforming retrovirus (AKT-8), which is known to cause leukemia in mice. AKT is the major downstream target of phosphatidylinositol 3-kinase (PI3K), which can be activated by receptor tyrosine kinases in response to various growth factors. AKT is a serine/threonine kinase located at the apex of a cascade of signaling pathways. Deregulated AKT signaling is implicated in cancer cell growth, proliferation, and survival. Novel antitumor strategies have now been developed to target AKT and key downstream targets in the clinic.

Keywords

AKT A-443654 Assessment AT13148 AT7867 CCT128930 GSK690693 Predictive biomarkers Therapeutics Fluorescence in situ hybridization (FISH) Phosphatidylinositol 3-kinase (PI3K) Protein kinase B. See AKT 

References

  1. Andjelkovic M, Alessi DR, Meier R, et al. Role of translocation in the activation and function of protein kinase B. J Biol Chem. 1997;272:31515–24.CrossRefPubMedGoogle Scholar
  2. Bellacosa A, Kumar CC, Di Cristofano A, Testa JR. Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res. 2005;94:29–86.CrossRefPubMedGoogle Scholar
  3. Bilodeau MT, Balitza AE, Hoffman JM, et al. Allosteric inhibitors of Akt1 and Akt2: a naphthyridinone with efficacy in an A2780 tumor xenograft model. Bioorg Med Chem Lett. 2008;18:3178–82.CrossRefPubMedGoogle Scholar
  4. Broderick DK, Di C, Parrett TJ, et al. Mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas. Cancer Res. 2004;64:5048–50.CrossRefPubMedGoogle Scholar
  5. Campbell IG, Russell SE, Choong DY, et al. Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res. 2004;64:7678–81.CrossRefPubMedGoogle Scholar
  6. Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as drug target in human cancer. J Clin Oncol. 2010;28:1075–83.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Di Cosimo S, Bendell JC, Cervantes-Ruiperez A, et al. A phase I study of the oral mTOR inhibitor ridaforolimus (RIDA) in combination with the IGF-1R antibody dalotuzumab (DALO) in patients (pts) with advanced solid tumors. J Clin Oncol. 2010;28:15s. suppl; abstr 3008.CrossRefGoogle Scholar
  8. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev. 2006;7:606–19.CrossRefGoogle Scholar
  9. Frech M, Andjelkovic M, Ingley E, Reddy KK, Falck JR, Hemmings BA. High affinity binding of inositol phosphates and phosphoinositides to the pleckstrin homology domain of RAC/protein kinase B and their influence on kinase activity. J Biol Chem. 1997;272:8474–81.CrossRefPubMedGoogle Scholar
  10. Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 2004;30:193–204.CrossRefPubMedGoogle Scholar
  11. Grimshaw KM, Hunter LJ, Yap TA, et al. AT7867 is a potent and oral inhibitor of AKT and p70 S6 kinase that induces pharmacodynamic changes and inhibits human tumor xenograft growth. Mol Cancer Ther. 2010;9:1100–10.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov. 2005;4:988–1004.CrossRefPubMedGoogle Scholar
  13. Luo Y, Shoemaker AR, Liu X, et al. Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo. Mol Cancer Ther. 2005;4:977–86.CrossRefPubMedGoogle Scholar
  14. Lyons J, Grimshaw K, Woodhead S, et al. AT13148, an orally bioavailable AKT kinase inhibitor with potent anti-tumor activity in both in vitro and in vivo models exhibiting AKT pathway deregulation. In: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics Abstract B251; 2007; 2007.Google Scholar
  15. Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1998;273:13375–8.CrossRefPubMedGoogle Scholar
  16. Murthy SS, Tosolini A, Taguchi T, Testa JR. Mapping of AKT3, encoding a member of the Akt/protein kinase B family, to human and rodent chromosomes by fluorescence in situ hybridization. Cytogenet Cell Genet. 2000;88:38–40.CrossRefPubMedGoogle Scholar
  17. Myers MP, Pass I, Batty IH, et al. The lipid phosphatase activity of PTEN is critical for its tumor suppressor function. Proc Natl Acad Sci U S A. 1998;95:13513–8.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Rhodes N, Heerding DA, Duckett DR, et al. Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity. Cancer Res. 2008;68:2366–74.CrossRefPubMedGoogle Scholar
  19. Samuels Y, Wang Z, Bardelli A, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304:554.CrossRefPubMedGoogle Scholar
  20. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307:1098–101.CrossRefPubMedGoogle Scholar
  21. Sarker D, Workman P. Pharmacodynamic biomarkers for molecular cancer therapeutics. Adv Cancer Res. 2007;96:213–68.CrossRefPubMedGoogle Scholar
  22. Shayesteh L, Lu Y, Kuo WL, et al. PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet. 1999;21:99–102.CrossRefPubMedGoogle Scholar
  23. Soung YH, Lee JW, Nam SW, Lee JY, Yoo NJ, Lee SH. Mutational analysis of AKT1, AKT2 and AKT3 genes in common human carcinomas. Oncology. 2006;70:285–9.CrossRefPubMedGoogle Scholar
  24. Tokunaga E, Kimura Y, Oki E, et al. Akt is frequently activated in HER2/neu-positive breast cancers and associated with poor prognosis among hormone-treated patients. Int J Cancer. 2006;118:284–9.CrossRefPubMedGoogle Scholar
  25. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501.CrossRefPubMedGoogle Scholar
  26. Yang ZZ, Tschopp O, Baudry A, Dummler B, Hynx D, Hemmings BA. Physiological functions of protein kinase B/Akt. Biochem Soc Trans. 2004;32:350–4.CrossRefPubMedGoogle Scholar
  27. Yap TA, Garrett MD, Walton MI, Raynaud F, de Bono JS, Workman P. Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises. Curr Opin Pharmacol. 2008;8:393–412.CrossRefPubMedGoogle Scholar
  28. Yap TA, Sandhu SK, Workman P, de Bono JS. Envisioning the future of early anticancer drug development. Nat Rev Cancer. 2010a;10(7):514–23, doi: 10.1038/nrc2870.Google Scholar
  29. Yap TA, Patnaik A, Fearen I, et al. First-in-class phase I trial of a selective Akt inhibitor, MK2206, evaluating alternate day and once weekly doses in advanced cancer patients with evidence of target modulation and antitumor activity. J Clin Oncol. 2010b;28:15s. suppl; abstr 3009.Google Scholar
  30. Yap TA, Walton MI, Hunter LJ, et al. Preclinical pharmacology, antitumor activity, and development of pharmacodynamic markers for the novel, potent AKT inhibitor CCT128930. Mol Cancer Ther. 2011;10:360–71.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Drug Development Unit, Royal Marsden NHS Foundation Trust, and The Institute of Cancer ResearchSuttonUK

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