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
. 2024 Jan 3;4(1):9-24.
doi: 10.21873/cdp.10279. eCollection 2024 Jan-Feb.

Development and Clinical Applications of PI3K/AKT/mTOR Pathway Inhibitors as a Therapeutic Option for Leukemias

Anna Karolyna DA Costa Machado  1 , Caio Bezerra Machado  1 , Flávia Melo Cunha DE Pinho Pessoa  1 , Igor Valentim Barreto  1 , Renan Brito Gadelha  1 , Deivide DE Sousa Oliveira  2 , Rodrigo Monteiro Ribeiro  2 , Germison Silva Lopes  3 , Manoel Odorico DE Moraesfilho  1 , Maria Elisabete Amaral DE Moraes  1 , André Salim Khayat  4 , Caroline Aquino Moreira-Nunes  1   4   5
Affiliations
Review

Development and Clinical Applications of PI3K/AKT/mTOR Pathway Inhibitors as a Therapeutic Option for Leukemias

Anna Karolyna DA Costa Machado et al. Cancer Diagn Progn. .

Abstract

Leukemias are hematological neoplasms characterized by dysregulations in several cellular signaling pathways, prominently including the PI3K/AKT/mTOR pathway. Since this pathway is associated with several important cellular mechanisms, such as proliferation, metabolism, survival, and cell death, its hyperactivation significantly contributes to the development of leukemias. In addition, it is a crucial prognostic factor, often correlated with therapeutic resistance. Changes in the PI3K/AKT/mTOR pathway are identified in more than 50% of cases of acute leukemia, especially in myeloid lineages. Furthermore, these changes are highly frequent in cases of chronic lymphocytic leukemia, especially those with a B cell phenotype, due to the correlation between the hyperactivation of B cell receptors and the abnormal activation of PI3Kδ. Thus, the search for new therapies that inhibit the activity of the PI3K/AKT/mTOR pathway has become the objective of several clinical studies that aim to replace conventional oncological treatments that have high rates of toxicities and low specificity with target-specific therapies offering improved patient quality of life. In this review we describe the PI3K/AKT/mTOR signal transduction pathway and its implications in leukemogenesis. Furthermore, we provide an overview of clinical trials that employed PI3K/AKT/mTOR inhibitors either as monotherapy or in combination with other cytotoxic agents for treating patients with various types of leukemias. The varying degrees of treatment efficacy are also reported.

Keywords: Leukemia; PI3K/AKT/mTOR; kinase inhibitors; molecular biomarkers; review; target therapy.

PubMed Disclaimer

Conflict of interest statement

The Authors declare no conflict of interest in relation to this study. The funders had no role in the design of the study; in the collection, analyses, or data interpretation; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1. PI3K/AKT/mTOR intracellular signaling. Activation of PI3KIA begins from receptor tyrosine kinases (RTKs), G-protein coupled receptors (GPCRs) or other cell-specific receptors, such as B-cell receptor (BCR), while the PI3KIB isoform is activated exclusively through GPCR signaling. Both types of activation induce conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) into phosphatidylinositol 3,4,5-triphosphate (PIP3), in a reaction that may be reversed through the inhibitory catalytic activity of phosphatase and tensin homolog (PTEN). PIP3 acts as a downstream messenger for activation of components of cellular pathways, including AKT serine/threonine kinase (AKT), which ultimately lead to cell cycle progression, apoptosis inhibition and maintenance of cell metabolism through regulation of major signaling proteins such as glycogen synthase kinase 3 (GSK3), forkhead box (FOXO), nuclear factor kappa B (NFkB) and tumor protein 53 (p53). AKT also activates downstream pathways important for cell homeostasis, including the mechanistic target of Rapamycin kinase (mTOR) activity, which corroborates AKT function in cell survival and regulation of metabolic activities. Downstream activation of component of inhibitor of nuclear factor kappa B kinase complex, conserved helix-loophelix ubiquitous kinase (CHUK), by AKT induces phosphorylation of both mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which are the main effectors of mTOR activity and lead to cell regulation and survival, but also to phosphorylation-mediated feedback activation of AKT.
Figure 2
Figure 2. Chemical structures and illustration of the catalytic region where PI3Kδ inhibition by Idelalisib occurs. All illustrations of the PI3Kδ protein presented in Figure 2 were acquired from the Swiss-Model server (https://swissmodel.expasy.org/repository/uniprot/O00329?model=AFO00329-F1-model-v4), whereas all Idelalisib inhibitor chemical structures were acquired from the PubChem server (https://pubchem.ncbi.nlm.nih.gov/compound/11625818#section=3D-Conformer). Furthermore, the assembly of the figure was performed on the Biorender virtual platform. A) Phosphatidylinositol 3-kinase delta (PI3Kδ) 3D structure; B) Idelalisib inhibitor 3D chemical structure; C) Illustration of the catalytic region of the PI3Kδ protein interacting with Idelalisib, in the way that the inhibitor competes for the binding of adenosine triphosphate (ATP) molecules on the protein and will form bonds between some of the chemical groups of the inhibitor and certain amino acid residues in the catalytic site, such as VAL 828, VAL 827, GLU 826 and ASP 911.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Nemkov T, D’Alessandro A, Reisz JA. Metabolic underpinnings of leukemia pathology and treatment. Cancer Rep (Hoboken) 2019;2(2):e1139. doi: 10.1002/cnr2.1139. - DOI - PMC - PubMed
    1. Khoury JD, Solary E, Abla O, Akkari Y, Alaggio R, Apperley JF, Bejar R, Berti E, Busque L, Chan JKC, Chen W, Chen X, Chng WJ, Choi JK, Colmenero I, Coupland SE, Cross NCP, De Jong D, Elghetany MT, Takahashi E, Emile JF, Ferry J, Fogelstrand L, Fontenay M, Germing U, Gujral S, Haferlach T, Harrison C, Hodge JC, Hu S, Jansen JH, Kanagal-Shamanna R, Kantarjian HM, Kratz CP, Li XQ, Lim MS, Loeb K, Loghavi S, Marcogliese A, Meshinchi S, Michaels P, Naresh KN, Natkunam Y, Nejati R, Ott G, Padron E, Patel KP, Patkar N, Picarsic J, Platzbecker U, Roberts I, Schuh A, Sewell W, Siebert R, Tembhare P, Tyner J, Verstovsek S, Wang W, Wood B, Xiao W, Yeung C, Hochhaus A. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and histiocytic/dendriticneoplasms. Leukemia. 2022;36(7):1703–1719. doi: 10.1038/s41375-022-01613-1. - DOI - PMC - PubMed
    1. Alaggio R, Amador C, Anagnostopoulos I, Attygalle AD, Araujo IBO, Berti E, Bhagat G, Borges AM, Boyer D, Calaminici M, Chadburn A, Chan JKC, Cheuk W, Chng WJ, Choi JK, Chuang SS, Coupland SE, Czader M, Dave SS, de Jong D, Du MQ, Elenitoba-Johnson KS, Ferry J, Geyer J, Gratzinger D, Guitart J, Gujral S, Harris M, Harrison CJ, Hartmann S, Hochhaus A, Jansen PM, Karube K, Kempf W, Khoury J, Kimura H, Klapper W, Kovach AE, Kumar S, Lazar AJ, Lazzi S, Leoncini L, Leung N, Leventaki V, Li XQ, Lim MS, Liu WP, Louissaint A Jr, Marcogliese A, Medeiros LJ, Michal M, Miranda RN, Mitteldorf C, Montes-Moreno S, Morice W, Nardi V, Naresh KN, Natkunam Y, Ng SB, Oschlies I, Ott G, Parrens M, Pulitzer M, Rajkumar SV, Rawstron AC, Rech K, Rosenwald A, Said J, Sarkozy C, Sayed S, Saygin C, Schuh A, Sewell W, Siebert R, Sohani AR, Tooze R, Traverse-Glehen A, Vega F, Vergier B, Wechalekar AD, Wood B, Xerri L, Xiao W. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid neoplasms. Leukemia. 2022;36(7):1720–1748. doi: 10.1038/s41375-022-01620-2. - DOI - PMC - PubMed
    1. Rose-Inman H, Kuehl D. Acute leukemia. Hematol Oncol Clin North Am. 2017;31(6):1011–1028. doi: 10.1016/j.hoc.2017.08.006. - DOI - PubMed
    1. Narayanan D, Weinberg OK. How I investigate acute myeloid leukemia. Int J Lab Hematol. 2020;42(1):3–15. doi: 10.1111/ijlh.13135. - DOI - PubMed

LinkOut - more resources