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

A. Lonetti, I. L. Antunes, F. Chiarini, E. Orsini, F. Buontempo, F. Ricci, P. L. Tazzari, P. Pagliaro, F. Melchionda, A. Pession, A. Bertaina, F. Locatelli, J. A. Mccubrey, J. T. Barata, A. M. Martelli

Research output: Contribution to journalArticlepeer-review

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 G 2 /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.

Original languageEnglish
Pages (from-to)1196-1206
Number of pages11
JournalLeukemia
Volume28
Issue number6
DOIs
Publication statusPublished - 2014

Keywords

  • apoptosis
  • cell cycle
  • chemotherapy
  • PI3K
  • T-cell acute lymphoblastic leukemia
  • targeted therapy

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

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