Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Nov 25:14:1517-1535.
doi: 10.2147/PGPM.S305068. eCollection 2021.

Clinical Development of AKT Inhibitors and Associated Predictive Biomarkers to Guide Patient Treatment in Cancer Medicine

Niamh Coleman  1 , Justin T Moyers  1   2 , Alice Harbery  3 , Igor Vivanco  4 , Timothy A Yap  1   5   6
Affiliations
Review

Clinical Development of AKT Inhibitors and Associated Predictive Biomarkers to Guide Patient Treatment in Cancer Medicine

Niamh Coleman et al. Pharmgenomics Pers Med. .

Abstract

The serine/threonine kinase AKT is a critical effector of the phosphoinositide 3-kinase (PI3K) signaling cascade and has a pivotal role in cell growth, proliferation, survival, and metabolism. AKT is one of the most commonly activated pathways in human cancer and dysregulation of AKT-dependent pathways is associated with the development and maintenance of a range of solid tumors. There are multiple small-molecule inhibitors targeting different components of the PI3K/AKT pathway currently at various stages of clinical development, in addition to new combination strategies aiming to boost the therapeutic efficacy of these drugs. Correlative and translational studies have been undertaken in the context of clinical trials investigating AKT inhibitors, however the identification of predictive biomarkers of response and resistance to AKT inhibition remains an unmet need. In this review, we discuss the biological function and activation of AKT, discuss its contribution to tumor development and progression, and review the efficacy and toxicity data from clinical trials, including both AKT inhibitor monotherapy and combination strategies with other agents. We also discuss the promise and challenges associated with the development of AKT inhibitors and associated predictive biomarkers of response and resistance.

Keywords: AKT; AKT inhibitor; PI3K; m-TOR.

PubMed Disclaimer

Conflict of interest statement

TAY: Research support (to Institution): AstraZeneca, Artios, Bayer, Beigene, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, GlaxoSmithKline, Genentech, ImmuneSensor, Ipsen, Jounce, Karyopharm, Kyowa, Merck, Novartis, Pfizer, Ribon Therapeutics, Repare, Regeneron, Sanofi, Scholar Rock, Seattle Genetics, Tesaro, and Vertex Pharmaceuticals. Consultancies: Almac, Aduro, AstraZeneca, Atrin, Axiom, Bayer, Bristol Myers Squibb, Calithera, Clovis, Cybrexa, EMD Serono, F-Star, Guidepoint, Ignyta, I-Mab, Jansen, Merck, Pfizer, Repare, Roche, Rubius, Schrodinger, Seattle Genetics, Varian and Zai Labs. IV: Non-financial support from Arqule Therapeutics, during the conduct of the study. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
(A) Structural domains of AKT. AKT1, AKT2 and AKT3 share common domain structure with other members of the cAMP‐dependent, cGMP‐dependent and protein kinase C (AGC) subfamily of protein kinases: this consists of an N‐terminus pleckstrin homology (PH) domain, a large central kinase domain and a C‐terminus hydrophobic domain. (B) The PI3K-AKT-mTOR pathway. A selection of the downstream targets of AKT is shown.
Figure 2
Figure 2
Frequency of AKT1 and AKT2 alterations from analysis of MSK-IMPACT Clinical Sequencing Cohort (MSKCC, Nat Med 2017), cBioPortal genomic database.,
See this image and copyright information in PMC

References

    1. Lawrence MS, Stojanov P, Mermel CH, et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature. 2014;505(7484):495–501. doi: 10.1038/nature12912 - DOI - PMC - PubMed
    1. Janku F, Yap TA, Meric-Bernstam F. Targeting the PI3K pathway in cancer: are we making headway? Nat Rev Clin Oncol. 2018;15(5):273–291. doi: 10.1038/nrclinonc.2018.28 - DOI - PubMed
    1. Clark AS, West K, Streicher S, Dennis PA. Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol Cancer Ther. 2002;1(9):707–717. doi: 10.1158/1535-7163.MCT-11-0712 - DOI - PubMed
    1. Mundi PS, Sachdev J, McCourt C, Kalinsky K. AKT in cancer: new molecular insights and advances in drug development. Br J Clin Pharmacol. 2016;82(4):943–956. doi: 10.1111/bcp.13021 - DOI - PMC - PubMed
    1. Hinz N, Jücker M. Distinct functions of AKT isoforms in breast cancer: a comprehensive review. Cell Communication and Signaling. 2019;17(1):1–29. doi: 10.1186/s12964-019-0450-3 - DOI - PMC - PubMed