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Review
. 2017 Apr:172:101-115.
doi: 10.1016/j.pharmthera.2016.12.001. Epub 2016 Dec 3.

Maximising the potential of AKT inhibitors as anti-cancer treatments

Jessica S Brown  1 , Udai Banerji  2
Affiliations
Review

Maximising the potential of AKT inhibitors as anti-cancer treatments

Jessica S Brown et al. Pharmacol Ther. 2017 Apr.

Abstract

PI3K/AKT signalling is commonly disrupted in human cancers, with AKT being a central component of the pathway, influencing multiple processes that are directly involved in tumourigenesis. Targeting AKT is therefore a highly attractive anti-cancer strategy with multiple AKT inhibitors now in various stages of clinical development. In this review, we summarise the role and regulation of AKT signalling in normal cellular physiology. We highlight the mechanisms by which AKT signalling can be hyperactivated in cancers and discuss the past, present and future clinical strategies for AKT inhibition in oncology.

Keywords: AKT; AKT inhibitors; Cancer; PI3K/AKT signalling; PKB.

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Conflict of interest statement

Conflict of Interest

Dr Udai Banerji is employed by The Institute of Cancer Research. The Institute of Cancer Research was involved in the discovery of the AKT inhibitor AZD536 and has commercial interests related to the drug. The author is not named on the patent and does not receive payment as part of rewards to inventors scheme related to AZD5363.

Figures

Figure 1
Figure 1
Structural domains of AKT.
Figure 2
Figure 2
Activation and negative regulation of AKT. See text for details.
Figure 3
Figure 3
Diagram illustrating feedback inhibition and activation within AKT signalling.
Figure 4
Figure 4
(A) Frequency of AKT1-3 amplification across a range of tumour types.. (B) AKT mutations are found in approximately 1% of all cancers. The frequency of AKT mutations vary between cancer types as shown. Data gathered from cbioportal.org database (Cerami et al. 2012; Gao et al. 2013). Only studies with n>100 included in analysis.
See this image and copyright information in PMC

References

    1. Abbadessa G, Eathiraj S, Meade J, Wick M, Tolcher A, Papadopoulos K, Saleh M, Sachdev J, Chai F, Schwartz B. Association of AKT1E17K and PIK3CAH1047R mutations with efficacy of ARQ 092 in vitro, in vivo and in patients. Molecular Cancer Therapeutics. 2015;14(12 Supplement 2):C134. doi: 10.1158/1535-7163.TARG-15-C134. - DOI
    1. Ahn DH, Li J, Wei L, Doyle A, Marshall JL, Schaaf LJ, Phelps MA, Villalona-Calero MA, Bekaii-Saab T. Results of an abbreviated phase-II study with the Akt Inhibitor MK-2206 in Patients with Advanced Biliary Cancer. Sci Rep. 2015;5:12122. - PMC - PubMed
    1. Alessi DR, Caudwell FB, Andjelkovic M, Hemmings BA, Cohen P. Molecular basis for the substrate specificity of protein kinase B; comparison with MAPKAP kinase-1 and p70 S6 kinase. FEBS Lett. 1996;399:333–338. - PubMed
    1. Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, Cohen P. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol. 1997;7:261–269. - PubMed
    1. Algazi AP, O’Brien K, Lencioni A, Tsai KK, Kadafour M, Chapman PB, Daud A. Phase II trial of trametinib in combination with the AKT inhibitor GSK 2141795 in BRAF wild-type melanoma. 2015

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