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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dc.contributor.authorSimioni, Carolina
dc.contributor.authorCani, Alice
dc.contributor.authorMartelli, Alberto M.
dc.contributor.authorZauli, Giorgio
dc.contributor.authorTabellini, Giovanna
dc.contributor.authorMcCubrey, James A.
dc.contributor.authorCapitani, Silvano
dc.contributor.authorNeri, Luca M.
dc.date.accessioned2016-06-14T13:40:10Z
dc.date.available2016-06-14T13:40:10Z
dc.date.issued2014-10
dc.description.abstractThe 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.en_US
dc.identifier.citationOncotarget; 5:20 p. 10034-10047en_US
dc.identifier.issn1949-2553
dc.identifier.pmidpmc4259403en_US
dc.identifier.urihttp://hdl.handle.net/10342/5575
dc.relation.urihttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4259403/en_US
dc.subjectB-pre acute lymphoblastic leukemiaen_US
dc.subjectTorin-2en_US
dc.subjectmTORen_US
dc.subjecttargeted therapyen_US
dc.subjectAkten_US
dc.titleActivity of the novel mTOR inhibitor Torin-2 in B-precursor acute lymphoblastic leukemia and its therapeutic potential to prevent Akt reactivationen_US
dc.typeArticleen_US
ecu.journal.issue20en_US
ecu.journal.nameOncotargeten_US
ecu.journal.pages10034-10047en_US
ecu.journal.volume5en_US

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