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

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

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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: luca.neri@unife.it

Silvano Capitani , email: silvano.capitani@unife.it

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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