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Dual Inhibition of Class IA Phosphatidylinositol 3-Kinase and Mammalian Target of Rapamycin as a New Therapeutic Option for T-Cell Acute Lymphoblastic Leukemia

¹ Department of Human Anatomical Sciences and ² Pediatric Oncology and Haematology Unit, University of Bologna, ³ Immunohaematology and Transfusion Center, Policlinico S.Orsola-Malpighi, and ⁴ IGM-Consiglio Nazionale delle Ricerche, Sezione di Bologna c/o I.O.R., Bologna, Italy; and ⁵ Department of Microbiology and Immunology, School of Medicine, East Carolina University, Greenville, North Carolina

Requests for reprints: Alberto M. Martelli, Dipartimento di Scienze Anatomiche Umane, Università di Bologna, 40126 Bologna, Italy. Phone: 39-0512091580; Fax: 39-051-2091695; E-mail: alberto.martelli{at}gmail.com.

Key Words: PI3K/Akt/mTOR signaling • apoptosis • caspases • drug resistance • combination therapy

Recent investigations have documented that constitutively activated phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL), where it strongly influences growth and survival. These findings lend compelling weight for the application of PI3K/Akt/mTOR inhibitors in T-ALL. However, our knowledge of PI3K/Akt/mTOR signaling in T-ALL is limited and it is not clear whether it could be an effective target for innovative therapeutic strategies. Here, we have analyzed the therapeutic potential of the dual PI3K/mTOR inhibitor PI-103, a small synthetic molecule of the pyridofuropyrimidine class, on both T-ALL cell lines and patient samples, which displayed constitutive activation of PI3K/Akt/mTOR signaling. PI-103 inhibited the growth of T-ALL cells, including 170-kDa P-glycoprotein overexpressing cells. PI-103 cytotoxicity was independent of p53 gene status. PI-103 was more potent than inhibitors that are selective only for PI3K (Wortmannin, LY294002) or for mTOR (rapamycin). PI-103 induced G₀-G₁ phase cell cycle arrest and apoptosis, which was characterized by activation of caspase-3 and caspase-9. PI-103 caused Akt dephosphorylation, accompanied by dephosphorylation of the Akt downstream target, glycogen synthase kinase-3β. Also, mTOR downstream targets were dephosphorylated in response to PI-103, including p70S6 kinase, ribosomal S6 protein, and 4E-BP1. PI-103 strongly synergized with vincristine. These findings indicate that multitargeted therapy toward PI3K and mTOR alone or with existing drugs may serve as an efficient treatment toward T-ALL cells, which require up-regulation of PI3K/Akt/mTOR signaling for their survival and growth. [Cancer Res 2009;69(8):3520–28]