Abstract
Over the past years, targeted therapies have received tremendous attention in cancer therapy. One of the most frequently targeted pathways is the PI3K/AKT/mTOR signaling pathway that regulates crucial cellular processes including proliferation, survival, and migration. In a wide variety of cancer entities, the PI3K/AKT/mTOR signaling pathway was found to be a critical driver of disease progression, indicating a noteworthy target in cancer therapy. This chapter focuses on targeted therapies against AKT, which is a key enzyme within the PI3K/AKT/mTOR pathway. Although the three different isoforms of AKT, namely AKT1, AKT2, and AKT3, have a high homology, the isoforms exhibit different biological functions. Recently, direct inhibitors against all AKT isoforms as well as selective inhibitors against specific AKT isoforms have been extensively investigated in preclinical work as well as in clinical trials to attenuate proliferation of cancer cells. While no AKT inhibitor has been approved by the FDA for cancer therapy to date, AKT still plays a crucial role in a variety of treatment strategies including immune checkpoint inhibition. In this chapter, we summarize the status of AKT inhibitors either targeting all or specific AKT isoforms. Furthermore, we explain the role of AKT signaling in direct inhibition of tumor cell growth as well as in immune cells and immune checkpoint inhibition.
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Abbreviations
- AKT:
-
AKT8 virus oncogene cellular homolog
- ATP:
-
Adenosine triphosphate
- AO:
-
Antisense oligonucleotide
- Bcl-xL:
-
B cell lymphoma-extra large
- BRAF:
-
V-raf murine sarcoma viral oncogene homolog B1
- COSMIC:
-
Catalog of Somatic Mutations in Cancer
- CTLA-4:
-
Cytotoxic T lymphocyte-associated protein 4
- CRC:
-
Colorectal carcinoma
- ER:
-
Estrogen receptor
- ERK:
-
Extracellular signal-regulated kinase
- FDA:
-
Food and Drug Administration
- FGF-2:
-
Fibroblast growth factor-2
- GSK3ß:
-
Glycogen synthase kinase 3 beta
- HER2:
-
Human epidermal growth factor receptor 2
- IC50:
-
Half maximal inhibitory concentration
- IL:
-
Interleukin
- ITIM:
-
Immunoreceptor tyrosine-based inhibition motif
- ITSM:
-
Immunoreceptor tyrosine-based switch motif
- JAK:
-
Janus kinase
- kDa:
-
Kilodalton
- MEK:
-
MAPK/ERK Kinase
- MHC:
-
Major histocompatibility complex
- mRNA:
-
Messenger RNA
- mTOR:
-
Mammalian target of rapamycin
- mTORC1:
-
MTOR complex 1
- NCT:
-
ClinicalTrials.gov identifier
- NSCLC:
-
Non-small-cell lung carcinoma
- OS:
-
Overall survival
- PD1:
-
Programmed cell death protein 1 receptor
- PDK1:
-
Phosphoinositide-dependent kinase-1
- PH:
-
Pleckstrin homology domain
- PI-3,4,5P3:
-
Phosphatidylinositol-3,4,5-trisphosphate
- PI3K:
-
Phosphoinositide-3-kinase
- PP2A:
-
Protein phosphatase 2
- PRAS40:
-
Proline-rich AKT substrate of 40 kDa
- PTEN:
-
Phosphatase and tensin homolog
- Raf:
-
Rat fibrosarcoma
- Ras:
-
Rat sarcoma
- RTK:
-
Receptor Tyrosine Kinase
- S6K1:
-
Ribosomal protein S6 kinase beta 1
- SHP2:
-
Src homology region 2 domain-containing phosphatase 2
- STAT:
-
Signal transducer and activator of transcription
- TCR:
-
T cell receptor
- TNF:
-
Tumor necrosis factor
- TRAIL:
-
TNF-related apoptosis-inducing ligand
- TSC2:
-
Tuberous sclerosis complex 2
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D.J.S. reviewed the literature, prepared the figure, and wrote the original draft of this chapter. M.J. critically revised the original draft.
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Smit, D.J., Jücker, M. (2022). AKT Isoforms as a Target in Cancer and Immunotherapy. In: Dominguez-Villar, M. (eds) PI3K and AKT Isoforms in Immunity . Current Topics in Microbiology and Immunology, vol 436. Springer, Cham. https://doi.org/10.1007/978-3-031-06566-8_18
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