Targeting the PI3K/Akt/mTOR Signaling Pathway in B-precursor Acute Lymphoblastic Leukemia and Its Therapeutic Potential

Overview

Journal Leukemia

Specialties Hematology
Oncology

Date 2013 Jul 30

PMID 23892718

Citations 73

Authors

L M Neri

A Cani

A M Martelli

C Simioni

C Junghanss

G Tabellini

F Ricci

P L Tazzari

P Pagliaro

J A McCubrey

S Capitani

Affiliations

Soon will be listed here.

Abstract

B-precursor acute lymphoblastic leukemia (B-pre ALL) is a malignant disorder characterized by the abnormal proliferation of B-cell progenitors. The prognosis of B-pre ALL has improved in pediatric patients, but the outcome is much less successful in adults. Constitutive activation of the phosphatidylinositol 3-kinase (PI3K), Akt and the mammalian target of rapamycin (mTOR) (PI3K/Akt/mTOR) network is a feature of B-pre ALL, where it strongly influences cell growth and survival. RAD001, a selective mTORC1 inhibitor, has been shown to be cytotoxic against many types of cancer including hematological malignancies. To investigate whether mTORC1 could represent a target in the therapy of B-pre ALL, we treated cell lines and adult patient primary cells with RAD001. We documented that RAD001 decreased cell viability, induced cell cycle arrest in G0/G1 phase and caused apoptosis in B-pre ALL cell lines. Autophagy was also induced, which was important for the RAD001 cytotoxic effect, as downregulation of Beclin-1 reduced drug cytotoxicity. RAD001 strongly synergized with the novel allosteric Akt inhibitor MK-2206 in both cell lines and patient samples. Similar results were obtained with the combination CCI-779 plus GSK 690693. These findings point out that mTORC1 inhibitors, either as a single agent or in combination with Akt inhibitors, could represent a potential therapeutic innovative strategy in B-pre ALL.

Citing Articles

Hedgehog and PI3K/Akt/mTOR Signaling Pathways Involvement in Leukemic Malignancies: Crosstalk and Role in Cell Death.

Sicurella M, De Chiara M, Neri L Cells. 2025; 14(4).

PMID: 39996741 PMC: 11853774. DOI: 10.3390/cells14040269.

Combination of JAKi and HDACi Exerts Antiangiogenic Potential in Cutaneous T-Cell Lymphoma.

Karagianni F, Piperi C, Valero-Diaz S, Amato C, Vaque J, Casar B Cancers (Basel). 2024; 16(18).

PMID: 39335148 PMC: 11430229. DOI: 10.3390/cancers16183176.

BRG1 promotes progression of B-cell acute lymphoblastic leukemia by disrupting PPP2R1A transcription.

Kang Q, Ma D, Zhao P, Chai X, Huang Y, Gao R Cell Death Dis. 2024; 15(8):621.

PMID: 39187513 PMC: 11347705. DOI: 10.1038/s41419-024-06996-w.

The potential role of RNA sequencing in diagnosing unexplained insensitivity to conventional chemotherapy in pediatric patients with B-cell acute lymphoblastic leukemia.

Li X, Huang Z, Zhu L, Lai W, Li Y, Chen H BMC Med Genomics. 2024; 17(1):149.

PMID: 38811988 PMC: 11137891. DOI: 10.1186/s12920-024-01892-w.

Not only a therapeutic target; mTOR in Hodgkin lymphoma and acute lymphoblastic leukemia.

Cuellar Mendoza M, Chavez Sanchez F, Dorantes Acosta E, Niembro Zuniga A, Pelayo R, Zapata Tarres M Front Oncol. 2024; 14:1304605.

PMID: 38444670 PMC: 10912149. DOI: 10.3389/fonc.2024.1304605.

References

Moorman A . The clinical relevance of chromosomal and genomic abnormalities in B-cell precursor acute lymphoblastic leukaemia. Blood Rev. 2012; 26(3):123-35. DOI: 10.1016/j.blre.2012.01.001. View

Brown V, Fang J, Alcorn K, Barr R, Kim J, Wasserman R . Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling. Proc Natl Acad Sci U S A. 2003; 100(25):15113-8. PMC: 299917. DOI: 10.1073/pnas.2436348100. View

Grabinski N, Ewald F, Hofmann B, Staufer K, Schumacher U, Nashan B . Combined targeting of AKT and mTOR synergistically inhibits proliferation of hepatocellular carcinoma cells. Mol Cancer. 2012; 11:85. PMC: 3545733. DOI: 10.1186/1476-4598-11-85. View

Silva A, Girio A, Cebola I, Santos C, Antunes F, Barata J . Intracellular reactive oxygen species are essential for PI3K/Akt/mTOR-dependent IL-7-mediated viability of T-cell acute lymphoblastic leukemia cells. Leukemia. 2011; 25(6):960-7. DOI: 10.1038/leu.2011.56. View

Zhou Y, You M, Young K, Lin P, Lu G, Medeiros L . Advances in the molecular pathobiology of B-lymphoblastic leukemia. Hum Pathol. 2012; 43(9):1347-62. DOI: 10.1016/j.humpath.2012.02.004. View

Avellino R, Romano S, Parasole R, Bisogni R, Lamberti A, Poggi V . Rapamycin stimulates apoptosis of childhood acute lymphoblastic leukemia cells. Blood. 2005; 106(4):1400-6. DOI: 10.1182/blood-2005-03-0929. View

DallArmi C, Devereaux K, Paolo G . The role of lipids in the control of autophagy. Curr Biol. 2013; 23(1):R33-45. PMC: 3587843. DOI: 10.1016/j.cub.2012.10.041. View

Ren H, Chen M, Yue P, Tao H, Owonikoko T, Ramalingam S . The combination of RAD001 and NVP-BKM120 synergistically inhibits the growth of lung cancer in vitro and in vivo. Cancer Lett. 2012; 325(2):139-46. PMC: 3433638. DOI: 10.1016/j.canlet.2012.06.018. View

Zhou H, Luo Y, Huang S . Updates of mTOR inhibitors. Anticancer Agents Med Chem. 2010; 10(7):571-81. PMC: 2980558. DOI: 10.2174/187152010793498663. View

10.

Floch N, Kinkade C, Kobayashi T, Aytes A, Lefebvre C, Mitrofanova A . Dual targeting of the Akt/mTOR signaling pathway inhibits castration-resistant prostate cancer in a genetically engineered mouse model. Cancer Res. 2012; 72(17):4483-93. PMC: 3432676. DOI: 10.1158/0008-5472.CAN-12-0283. View

11.

Driscoll B, Tang A, Hu Y, Yan C, Fu Y, Luo Y . Discovery of a regulatory motif that controls the exposure of specific upstream cyclin-dependent kinase sites that determine both conformation and growth suppressing activity of pRb. J Biol Chem. 1999; 274(14):9463-71. DOI: 10.1074/jbc.274.14.9463. View

12.

Martelli A, Chiarini F, Evangelisti C, Cappellini A, Buontempo F, Bressanin D . Two hits are better than one: targeting both phosphatidylinositol 3-kinase and mammalian target of rapamycin as a therapeutic strategy for acute leukemia treatment. Oncotarget. 2012; 3(4):371-94. PMC: 3380573. DOI: 10.18632/oncotarget.477. View

13.

Levy D, Kahana J, Kumar R . AKT inhibitor, GSK690693, induces growth inhibition and apoptosis in acute lymphoblastic leukemia cell lines. Blood. 2008; 113(8):1723-9. DOI: 10.1182/blood-2008-02-137737. View

14.

Hirai H, Sootome H, Nakatsuru Y, Miyama K, Taguchi S, Tsujioka K . MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol Cancer Ther. 2010; 9(7):1956-67. DOI: 10.1158/1535-7163.MCT-09-1012. View

15.

Aziz S, Jilaveanu L, Zito C, Camp R, Rimm D, Conrad P . Vertical targeting of the phosphatidylinositol-3 kinase pathway as a strategy for treating melanoma. Clin Cancer Res. 2010; 16(24):6029-39. PMC: 3058635. DOI: 10.1158/1078-0432.CCR-10-1490. View

16.

Ewald F, Grabinski N, Grottke A, Windhorst S, Norz D, Carstensen L . Combined targeting of AKT and mTOR using MK-2206 and RAD001 is synergistic in the treatment of cholangiocarcinoma. Int J Cancer. 2013; 133(9):2065-76. DOI: 10.1002/ijc.28214. View

17.

Tan S, Ng Y, James D . Next-generation Akt inhibitors provide greater specificity: effects on glucose metabolism in adipocytes. Biochem J. 2011; 435(2):539-44. DOI: 10.1042/BJ20110040. View

18.

Thomas G . mTOR and cancer: reason for dancing at the crossroads?. Curr Opin Genet Dev. 2005; 16(1):78-84. DOI: 10.1016/j.gde.2005.12.003. View

19.

Vignot S, Faivre S, Aguirre D, Raymond E . mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol. 2005; 16(4):525-37. DOI: 10.1093/annonc/mdi113. View

20.

Levine B, Kroemer G . Autophagy in aging, disease and death: the true identity of a cell death impostor. Cell Death Differ. 2008; 16(1):1-2. PMC: 2717606. DOI: 10.1038/cdd.2008.139. View