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Review
. 2023 Nov 5;15(21):5297.
doi: 10.3390/cancers15215297.

PI3K/Akt/mTOR Signaling Pathway in Blood Malignancies-New Therapeutic Possibilities

Wojciech Wiese  1 , Julia Barczuk  1 , Olga Racinska  1 , Natalia Siwecka  1 , Wioletta Rozpedek-Kaminska  1 , Artur Slupianek  2 , Radoslaw Sierpinski  3 , Ireneusz Majsterek  1
Affiliations
Review

PI3K/Akt/mTOR Signaling Pathway in Blood Malignancies-New Therapeutic Possibilities

Wojciech Wiese et al. Cancers (Basel). .

Abstract

Blood malignancies remain a therapeutic challenge despite the development of numerous treatment strategies. The phosphatidylinositol-3 kinase (PI3K)/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway plays a central role in regulating many cellular functions, including cell cycle, proliferation, quiescence, and longevity. Therefore, dysregulation of this pathway is a characteristic feature of carcinogenesis. Increased activation of PI3K/Akt/mTOR signaling enhances proliferation, growth, and resistance to chemo- and immunotherapy in cancer cells. Overactivation of the pathway has been found in various types of cancer, including acute and chronic leukemia. Inhibitors of the PI3K/Akt/mTOR pathway have been used in leukemia treatment since 2014, and some of them have improved treatment outcomes in clinical trials. Recently, new inhibitors of PI3K/Akt/mTOR signaling have been developed and tested both in preclinical and clinical models. In this review, we outline the role of the PI3K/Akt/mTOR signaling pathway in blood malignancies' cells and gather information on the inhibitors of this pathway that might provide a novel therapeutic opportunity against leukemia.

Keywords: Akt inhibitors; PI3K inhibitors; PI3K/Akt/mTOR pathway; dual PI3K/mTOR inhibitors; leukemia; mTOR inhibitors.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of the main molecular consequences of phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway activation. Stimulation of growth factor receptor activates PI3K, which in turn causes phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3). This process can be reversed by phosphatase and tensin homolog (PTEN). Increased activity of PIP3 results in recruitment of phosphoinositide-dependent kinase 1 (PDK1), which subsequently phosphorylates and activates Akt. Activation of Akt degrades p53, increases protein synthesis, and inhibits the activity of several proapoptotic proteins. Akt, through activation of mTOR, enables the formation of the two complexes—mTORC1 and mTORC2. mTORC1 phosphorylates and activates eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and p70S6 kinase (p70S6K), which are responsible for cell growth and protein synthesis. mTORC2, on the other hand, regulates cytoskeletal architecture through protein kinase C (PKC) phosphorylation.
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