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Review
. 2022 Mar 24:12:819128.
doi: 10.3389/fonc.2022.819128. eCollection 2022.

PI3K/Akt/mTOR Pathway and Its Role in Cancer Therapeutics: Are We Making Headway?

Yan Peng  1 , Yuanyuan Wang  2 , Cheng Zhou  3 , Wuxuan Mei  2 , Changchun Zeng  3
Affiliations
Review

PI3K/Akt/mTOR Pathway and Its Role in Cancer Therapeutics: Are We Making Headway?

Yan Peng et al. Front Oncol. .

Abstract

Cancer is a severe public health issue that is a leading cause of mortality globally. It is also an impediment to improving life expectancy worldwide. Furthermore, the global burden of cancer incidence and death is continuously growing. Current therapeutic options are insufficient for patients, and tumor complexity and heterogeneity necessitate customized medicine or targeted therapy. It is critical to identify potential cancer therapeutic targets. Aberrant activation of the PI3K/AKT/mTOR pathway has a significant role in carcinogenesis. This review summarized oncogenic PI3K/Akt/mTOR pathway alterations in cancer and various cancer hallmarks associated with the PI3K/AKT/mTOR pathway, such as cell proliferation, autophagy, apoptosis, angiogenesis, epithelial-to-mesenchymal transition (EMT), and chemoresistance. Importantly, this review provided recent advances in PI3K/AKT/mTOR inhibitor research. Overall, an in-depth understanding of the association between the PI3K/AKT/mTOR pathway and tumorigenesis and the development of therapies targeting the PI3K/AKT/mTOR pathway will help make clinical decisions.

Keywords: PI3K/Akt/mTOR pathway; cancer; oncogenic alterations; precision medicine; targeted therapy.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Timeline of The Food and Drug Administration (FDA)-approved or the National Comprehensive Cancer Network (NCCN) recommended inhibitors targeting the PI3K/AKT/mTOR pathway in solid tumors. WM, Waldenstrom macroglobulinemia; LPL, lymphoplasmacytic lymphoma; RCC, renal cell carcinoma; SEGA, subependymal giant cell astrocytoma; TSC, tuberous sclerosis complex; NET, neuroendocrine tumor; GI, gastrointestinal.
Figure 2
Figure 2
Structure of class IA PI3K, mTORC1, mTORC2, AKT1, AKT2, AKT3, and PTEN from Uniprot.org. (A) class IA PI3K consists of catalytic and regulatory subunits. (B) mTORC1 subunits and corresponding binding sites on mTOR. (C) mTORC2 subunits and corresponding binding sites on mTOR. (D) Structure of AKT1. (E) Structure of AKT2. (F) Structure of AKT3. (G) Structure of PTEN. RBD, Ras binding domain; P, proline-rich domain; BH, breakpoint cluster homology domain; C2, membrane-interacting domain; iSH2, inter-SH2 domain; FRB, FKBP12-rapamycin-binding; HEAT, Huntingtin/Elongation factor 3/a subunit of protein phosphatase2A/TOR1; mSIN1, mammalian stress-activated; PH, pleckstrin homology; CAT, catalytic domain; HM, hydrophobic motif.
Figure 3
Figure 3
Schematic representation of the PI3K/Akt/mTOR pathway and its related inhibitors in solid tumors. The activation of the PI3K/Akt/mTOR pathway is associated with cell proliferation, autophagy, apoptosis, angiogenesis, EMT, and chemoresistance in solid tumors. GF, growth factor; EMT, epithelial-to-mesenchymal transition; RTK, tyrosine kinase receptor.
See this image and copyright information in PMC

References

    1. Foster KG, Fingar DC. Mammalian Target of Rapamycin (mTOR): Conducting the Cellular Signaling Symphony. J Biol Chem (2010) 285(19):14071–7. doi: 10.1074/jbc.R109.094003 - DOI - PMC - PubMed
    1. Kim LC, Cook RS, Chen J. Mtorc1 and Mtorc2 in Cancer and the Tumor Microenvironment. Oncogene (2017) 36(16):2191–201. doi: 10.1038/onc.2016.363 - DOI - PMC - PubMed
    1. Lee BJ, Boyer JA, Burnett GL, Thottumkara AP, Tibrewal N, Wilson SL, et al. . Selective Inhibitors of Mtorc1 Activate 4EBP1 and Suppress Tumor Growth. Nat Chem Biol (2021) 17(10):1065–74. doi: 10.1038/s41589-021-00813-7 - DOI - PMC - PubMed
    1. Luciani A, Stagi M. How Mtorc1 Makes Sense of Nutrients. Kidney Int (2021) 99(2):295–8. doi: 10.1016/j.kint.2020.07.052 - DOI - PubMed
    1. Wipperman MF, Montrose DC, Gotto AM, Jr, Hajjar DP. Mammalian Target of Rapamycin: A Metabolic Rheostat for Regulating Adipose Tissue Function and Cardiovascular Health. Am J Pathol (2019) 189(3):492–501. doi: 10.1016/j.ajpath.2018.11.013 - DOI - PMC - PubMed

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