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Molecular Targets for Therapy

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

Leukemia volume 28, pages 1196–1206 (2014)Cite this article

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Abstract

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.

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Acknowledgements

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.

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  1. A Lonetti and I L Antunes: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

    A Lonetti, E Orsini, F Buontempo & A M Martelli

  2. Cancer Biology Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal

    I L Antunes & J T Barata

  3. Institute of Molecular Genetics, National Research Council, Pavia, Italy

    F Chiarini & A M Martelli

  4. Muscoloskeletal Cell Biology Laboratory, IOR, Bologna, Italy

    F Chiarini & A M Martelli

  5. Immunohematology and Transfusion Center, Policlinico S.Orsola-Malpighi, Bologna, Italy

    F Ricci, P L Tazzari & P Pagliaro

  6. Clinica Pediatrica, University of Bologna, Policlinico S.Orsola-Malpighi, Bologna, Italy

    F Melchionda & A Pession

  7. Oncoematologia Pediatrica, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy

    A Bertaina & F Locatelli

  8. Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA

    J A McCubrey

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Lonetti, A., Antunes, I., Chiarini, F. et al. Activity of the pan-class I phosphoinositide 3-kinase inhibitor NVP-BKM120 in T-cell acute lymphoblastic leukemia. Leukemia 28, 1196–1206 (2014). https://doi.org/10.1038/leu.2013.369

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