Activity of the pan-class I phosphoinositide 3-kinase inhibitor NVP-BKM120 in T-cell acute lymphoblastic leukemia

• Published in: Leukemia Vol. 28; no. 6; pp. 1196 - 1206
• Main Authors: Lonetti, A., Antunes, Isabel Lobo, Chiarini, F., Orsini, E., Buontempo, F., Ricci, F., Tazzari, P. L., Pagliaro, P., Melchionda, F., Pession, A., Bertaina, A., Locatelli, F., McCubrey, J. A., Barata, João, Martelli, A. M.
• Format: Journal Article
• Language: English
• Published: London Springer Nature 01.06.2014; Nature Publishing Group UK; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; 631/80/82/23; 631/80/86; 692/699/67/1059/99; 692/699/67/1990/283/2125; Acute lymphoblastic leukemia; Acute lymphocytic leukemia; AKT protein; Aminopyridines - pharmacology; Animals; Antimitotic agents; Antineoplastic agents; Apoptosis; Apoptosis - drug effects; Bioavailability; Biology; Blotting, Western; Bone marrow; Cancer Research; Cell cycle; Cell Cycle - drug effects; Cell growth; Cell proliferation; Cell Proliferation - drug effects; Cell survival; Chemotherapy; Clinical trials; Critical Care Medicine; Cytotoxicity; Dephosphorylation; Drug dosages; Drug resistance; Drug therapy; Enzyme inhibitors; Flow Cytometry; Health aspects; Hematology; Humans; Intensive; Internal Medicine; Kinases; Leukemia; Lymphatic leukemia; Lymphoblasts; Lymphocytes T; Medical prognosis; Medicine; Medicine & Public Health; Mice; Mice, Inbred NOD; Mice, SCID; Microenvironments; Morpholines - pharmacology; Oncology; original-article; Patients; Phosphatase; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Physiological aspects; PI3K; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Protein kinases; Proteins; Signal transduction; Signaling; Solid tumors; Stromal cells; Survival; Targeted therapy; Time dependence; Tumor Cells, Cultured; Tumors; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation; United States; Italy; targeted therapy; apoptosis; PI3K; cell cycle; chemotherapy; T-cell acute lymphoblastic leukemia
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2013.369

© 2014 Macmillan Publishers Limited All rights reserved Constitutively active phosphoinositide 3-kinase (PI3K) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL), where it upregulates cell proliferation, survival and drug resistance. These observations lend compelling weight to the application of PI3K inhibitors in the therapy of T-ALL. Here, we have analyzed the therapeutic potential of the pan-PI3K inhibitor NVP-BKM120 (BKM120), an orally bioavailable 2,6-dimorpholino pyrimidine derivative, which has entered clinical trials for solid tumors, on both T-ALL cell lines and patient samples. BKM120 treatment resulted in G2/M phase cell cycle arrest and apoptosis, being cytotoxic to a panel of T-ALL cell lines and patient T lymphoblasts, and promoting a dose- and time-dependent dephosphorylation of Akt and S6RP. BKM120 maintained its pro-apoptotic activity against Jurkat cells even when cocultured with MS-5 stromal cells, which mimic the bone marrow microenvironment. Remarkably, BKM120 synergized with chemotherapeutic agents currently used for treating T-ALL patients. Moreover, in vivo administration of BKM120 to a subcutaneous xenotransplant model of human T-ALL significantly delayed tumor growth, thus prolonging survival time. Taken together, our findings indicate that BKM120, either alone or in combination with chemotherapeutic drugs, may be an efficient treatment for T-ALLs that have aberrant upregulation of the PI3K signaling pathway. This work was supported by a grant from MIUR FIRB 2010 (RBAP10447J_003) to AMM and by grants PTDC/SAU-OBD/104816/2008 and PTDC/SAU-ONC/122428/2010 from Fundação para a Ciência e a Tecnologia (FCT), Portugal, to JTB. ILA received a postdoctoral fellowship (SFRH/BPD/63920/2009) from FCT. FL was supported by Special Project AIRC 5x1000 n. 9962 and Progetto di rilevante Interesse Nazionale, PRIN 2010.