期刊
ONCOTARGET
卷 5, 期 20, 页码 10034-10047出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.2490
关键词
B-pre acute lymphoblastic leukemia; Torin-2; mTOR; targeted therapy; Akt
资金
- MIUR FIRB [RBAP10Z7FS_002, RBAP10447J_003]
- MIUR PRIN grant
- IRCCS Burlo Garofolo
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 G(0)/G(1) 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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