The PI3Kδ inhibitor idelalisib inhibits homing in an in vitro and in vivo model of B ALL

Etai Adam, Hye Na Kim, Eun Ji Gang, Caitlin Schnair, Solomon Lee, Solah Lee, Sajad Khazal, Osanna Kosoyan, Marina Konopleva, Chintan Parekh, Deepa Bhojwani, Alan S. Wayne, Hisham Abdel-Azim, Nora Heisterkamp, Yong Mi Kim

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

The quest continues for targeted therapies to reduce the morbidity of chemotherapy and to improve the response of resistant leukemia. Adhesion of acute lymphoblastic leukemia (ALL) cells to bone marrow stromal cells triggers intracellular signals that promote cell-adhesion-mediated drug resistance (CAM-DR). Idelalisib, an U.S. Food and Drug Administration (FDA)-approved PI3Kδ-specific inhibitor has been shown to be effective in CLL in down-regulating p-Akt and prolonging survival in combination with Rituximab; herein we explore the possibility of its use in B ALL and probe the mechanism of action. Primary B ALL in contact with OP9 stromal cells showed increased p-Aktser473. Idelalisib decreased p-Akt in patient samples of ALL with diverse genetic lesions. Addition of idelalisib to vincristine inhibited proliferation when compared to vincristine monotherapy in a subset of samples tested. Idelalisib inhibited ALL migration to SDF-1α in vitro and blocked homing of ALL cells to the bone marrow in vivo. This report tests PI3Kδ inhibitors in a more diverse group of ALL than has been previously reported and is the first published report of idelalisib inhibiting homing of ALL cells to bone marrow. Our data support further pre-clinical evaluation of idelalisib for the therapy of B ALL.

Original languageEnglish (US)
Article number121
JournalCancers
Volume9
Issue number9
DOIs
StatePublished - Sep 10 2017

Keywords

  • ALL
  • CAM-DR
  • Drug resistance
  • Idelalisib
  • Leukemia
  • Migration
  • Mouse model
  • PI3K

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Adam, E., Kim, H. N., Gang, E. J., Schnair, C., Lee, S., Lee, S., Khazal, S., Kosoyan, O., Konopleva, M., Parekh, C., Bhojwani, D., Wayne, A. S., Abdel-Azim, H., Heisterkamp, N., & Kim, Y. M. (2017). The PI3Kδ inhibitor idelalisib inhibits homing in an in vitro and in vivo model of B ALL. Cancers, 9(9), [121]. https://doi.org/10.3390/cancers9090121