Efficacy of Dual PI-3K and MTOR Inhibitors in Vitro and in Vivo in Acute Lymphoblastic Leukemia

Overview

Journal Oncotarget

Specialty Oncology

Date 2014 Nov 1

PMID 25361005

Citations 22

Authors

Jacky Wong

Robert Welschinger

John Hewson

Kenneth F Bradstock

Linda J Bendall

Affiliations

Soon will be listed here.

Abstract

The major regulators of human acute lymphoblastic leukemia (ALL) cell growth and survival mediate their effects through the phosphoinositide 3-kinase (PI-3K)/mammalian target of rapamycin (mTOR) pathway. We have shown that the mTOR inhibitor everolimus extended survival in a non-obese diabetic/severe combined immune-deficient (NOD/SCID) mouse xenograft model of human ALL. Since PI-3K has mTOR dependent and independent functions we examined the effect of the dual PI-3K/mTOR inhibitors BEZ235 and BGT226. These agents inhibited the proliferation of ALL cell lines with a three log greater potency than everolimus. However, the induction of cell death differed, with BGT226 being cytotoxic in the low micromolar range while a two log higher concentration of BEZ235 was required to produce the same effect. While all three agents extended the survival of NOD/SCID mice engrafted with human ALL, the responses of individual xenografts varied. Although differential phosphorylation of AKT on Ser(473) and Thr(308) in response to everolimus exposure was observed, this did not entirely explain the different in vivo responses to the drugs. Our data suggests that while dual PI-3K/mTOR inhibitors may improve therapeutic outcomes for a subset of ALL patients, patient selection will be important, with some patients likely to respond better to single mTOR inhibition.

Citing Articles

Overcoming Steroid Resistance in Pediatric Acute Lymphoblastic Leukemia-The State-of-the-Art Knowledge and Future Prospects.

Kosmider K, Karska K, Kozakiewicz A, Lejman M, Zawitkowska J Int J Mol Sci. 2022; 23(7).

PMID: 35409154 PMC: 8999045. DOI: 10.3390/ijms23073795.

Overcoming Glucocorticoid Resistance in Acute Lymphoblastic Leukemia: Repurposed Drugs Can Improve the Protocol.

Olivas-Aguirre M, Torres-Lopez L, Pottosin I, Dobrovinskaya O Front Oncol. 2021; 11:617937.

PMID: 33777761 PMC: 7991804. DOI: 10.3389/fonc.2021.617937.

Dual Kinase Targeting in Leukemia.

Mologni L, Marzaro G, Redaelli S, Zambon A Cancers (Basel). 2021; 13(1).

PMID: 33401428 PMC: 7796318. DOI: 10.3390/cancers13010119.

A dual PI3 kinase/mTOR inhibitor BEZ235 reverses doxorubicin resistance in ABCB1 overexpressing ovarian and pancreatic cancer cell lines.

Durrant D, Das A, Dyer S, Kukreja R Biochim Biophys Acta Gen Subj. 2020; 1864(6):129556.

PMID: 32061787 PMC: 10845210. DOI: 10.1016/j.bbagen.2020.129556.

Human BCR/ABL1 induces chronic myeloid leukemia-like disease in zebrafish.

Xu M, Ye Y, Ye Z, Xu S, Liu W, Xu J Haematologica. 2019; 105(3):674-686.

PMID: 31289206 PMC: 7049331. DOI: 10.3324/haematol.2019.215939.

References

Juarez J, Bradstock K, Gottlieb D, Bendall L . Effects of inhibitors of the chemokine receptor CXCR4 on acute lymphoblastic leukemia cells in vitro. Leukemia. 2003; 17(7):1294-300. DOI: 10.1038/sj.leu.2402998. View

Badura S, Tesanovic T, Pfeifer H, Wystub S, Nijmeijer B, Liebermann M . Differential effects of selective inhibitors targeting the PI3K/AKT/mTOR pathway in acute lymphoblastic leukemia. PLoS One. 2013; 8(11):e80070. PMC: 3828226. DOI: 10.1371/journal.pone.0080070. View

Manabe A, Coustan-Smith E, Behm F, Raimondi S, Campana D . Bone marrow-derived stromal cells prevent apoptotic cell death in B-lineage acute lymphoblastic leukemia. Blood. 1992; 79(9):2370-7. View

Bendall L, Kortlepel K, Gottlieb D . Human acute myeloid leukemia cells bind to bone marrow stroma via a combination of beta-1 and beta-2 integrin mechanisms. Blood. 1993; 82(10):3125-32. View

SCHULER W, Sedrani R, Cottens S, Haberlin B, Schulz M, Schuurman H . SDZ RAD, a new rapamycin derivative: pharmacological properties in vitro and in vivo. Transplantation. 1997; 64(1):36-42. DOI: 10.1097/00007890-199707150-00008. View

Pullen N, Dennis P, Andjelkovic M, Dufner A, Kozma S, Hemmings B . Phosphorylation and activation of p70s6k by PDK1. Science. 1998; 279(5351):707-10. DOI: 10.1126/science.279.5351.707. View

Le Good J, ZIEGLER W, Parekh D, Alessi D, Cohen P, Parker P . Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1. Science. 1998; 281(5385):2042-5. DOI: 10.1126/science.281.5385.2042. View

Cardone M, Roy N, Stennicke H, Salvesen G, Franke T, Stanbridge E . Regulation of cell death protease caspase-9 by phosphorylation. Science. 1998; 282(5392):1318-21. DOI: 10.1126/science.282.5392.1318. View

Diehl J, Cheng M, Roussel M, Sherr C . Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 1998; 12(22):3499-511. PMC: 317244. DOI: 10.1101/gad.12.22.3499. View

10.

Brunet A, Bonni A, Zigmond M, Lin M, Juo P, Hu L . Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999; 96(6):857-68. DOI: 10.1016/s0092-8674(00)80595-4. View

11.

Sarbassov D, Guertin D, Ali S, Sabatini D . Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005; 307(5712):1098-101. DOI: 10.1126/science.1106148. View

12.

Bendall L, Baraz R, Juarez J, Shen W, Bradstock K . Defective p38 mitogen-activated protein kinase signaling impairs chemotaxic but not proliferative responses to stromal-derived factor-1alpha in acute lymphoblastic leukemia. Cancer Res. 2005; 65(8):3290-8. DOI: 10.1158/0008-5472.CAN-04-3402. View

13.

Teachey D, Obzut D, Cooperman J, Fang J, Carroll M, Choi J . The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL. Blood. 2005; 107(3):1149-55. PMC: 1895910. DOI: 10.1182/blood-2005-05-1935. View

14.

Chow S, Minden M, Hedley D . Constitutive phosphorylation of the S6 ribosomal protein via mTOR and ERK signaling in the peripheral blasts of acute leukemia patients. Exp Hematol. 2006; 34(9):1183-91. DOI: 10.1016/j.exphem.2006.05.002. View

15.

Muller C, Miller C, Hofmann W, Gross M, Walsh C, Kawamata N . Rare mutations of the PIK3CA gene in malignancies of the hematopoietic system as well as endometrium, ovary, prostate and osteosarcomas, and discovery of a PIK3CA pseudogene. Leuk Res. 2006; 31(1):27-32. DOI: 10.1016/j.leukres.2006.04.011. View

16.

Fielding A, Richards S, Chopra R, Lazarus H, Litzow M, Buck G . Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2006; 109(3):944-50. DOI: 10.1182/blood-2006-05-018192. View

17.

Juarez J, Baraz R, Gaundar S, Bradstock K, Bendall L . Interaction of interleukin-7 and interleukin-3 with the CXCL12-induced proliferation of B-cell progenitor acute lymphoblastic leukemia. Haematologica. 2007; 92(4):450-9. DOI: 10.3324/haematol.10621. View

18.

Juarez J, Dela Pena A, Baraz R, Hewson J, Khoo M, Cisterne A . CXCR4 antagonists mobilize childhood acute lymphoblastic leukemia cells into the peripheral blood and inhibit engraftment. Leukemia. 2007; 21(6):1249-57. DOI: 10.1038/sj.leu.2404684. View

19.

Armstrong G, Sklar C, Hudson M, Robison L . Long-term health status among survivors of childhood cancer: does sex matter?. J Clin Oncol. 2007; 25(28):4477-89. DOI: 10.1200/JCO.2007.11.2003. View

20.

Montiel-Duarte C, Cordeu L, Agirre X, Roman-Gomez J, Jimenez-Velasco A, Jose-Eneriz E . Resistance to Imatinib Mesylate-induced apoptosis in acute lymphoblastic leukemia is associated with PTEN down-regulation due to promoter hypermethylation. Leuk Res. 2007; 32(5):709-16. DOI: 10.1016/j.leukres.2007.09.005. View