Oncotarget

Research Papers:

Activity of the novel mTOR inhibitor Torin-2 in B-precursor acute lymphoblastic leukemia and its therapeutic potential to prevent Akt reactivation

Carolina Simioni, Alice Cani, Alberto M. Martelli, Giorgio Zauli, Giovanna Tabellini, James McCubrey, Silvano Capitani and Luca M. Neri _

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Oncotarget. 2014; 5:10034-10047. https://doi.org/10.18632/oncotarget.2490

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Abstract

Carolina Simioni1,*, Alice Cani1,*, Alberto M. Martelli2, Giorgio Zauli3, Giovanna Tabellini4, James McCubrey5, Silvano Capitani1,6 and Luca M. Neri1

1 Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy

2 Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

3 Institute for Maternal and Child Health, IRCCS “Burlo Garofolo”, Trieste, Italy

4 Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy

5 Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA

6 LTTA Center, University of Ferrara, Ferrara, Italy

* These authors contributed equally to this work

Correspondence:

Luca M. Neri, email:

Silvano Capitani , email:

Keywords: B-pre acute lymphoblastic leukemia, Torin-2, mTOR, targeted therapy, Akt

Received: July 31, 2014 Accepted: September 15, 2014 Published: September 16, 2014

Abstract

The PI3K/Akt/mTOR signaling cascade is a key regulatory pathway controlling cell growth and survival, and its dysregulation is a reported feature of B-precursor acute lymphoblastic leukemia (B-pre ALL).

Torin-2 is a novel, second-generation ATP-competitive inhibitor that is potent and selective for mTOR with a superior pharmacokinetic profile to previous inhibitors. It has been shown that Torin-2 displayed dramatic antiproliferative activity across a panel of cancer cell lines.

To investigate if Torin-2 could represent a new option for the treatment of B-pre ALL, we tested its activity on a panel of B-pre ALL cell lines. In all of them Torin-2 showed a powerful cytotoxic activity, inhibiting the growth of each cell line in a dose-dependent manner, with an IC50 in the nanomolar range. Torin-2 caused both apoptosis and autophagy, induced cell cycle arrest in G0/G1 phase and affected both mTORC1 and mTORC2 activities as assessed by their specific substrate dephosphorylation.

Torin-2 alone suppressed feedback activation of PI3K/Akt, whereas the mTORC1 inhibitor RAD001 required the addition of the Akt inhibitor MK-2206 to achieve the same effect. These pharmacological strategies targeting PI3K/Akt/mTOR at different points of the signaling pathway cascade might represent a new promising therapeutic strategy for treatment of B-pre ALL patients.


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