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, Luca M. Neri

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)10034-10047
Number of pages14
JournalOncotarget
Volume5
Issue number20
Publication statusPublished - 2014

Keywords

  • Akt
  • B-pre acute lymphoblastic leukemia
  • mTOR
  • Targeted therapy
  • Torin-2

ASJC Scopus subject areas

  • Oncology

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    Simioni, C., Cani, A., Martelli, A. M., Zauli, G., Tabellini, G., McCubrey, J., Capitani, S., & Neri, L. M. (2014). Activity of the novel mTOR inhibitor Torin-2 in B-precursor acute lymphoblastic leukemia and its therapeutic potential to prevent Akt reactivation. Oncotarget, 5(20), 10034-10047.