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Oncotarget. 2017 Jul 28;8(35):57948-57963. doi: 10.18632/oncotarget.19678. eCollection 2017 Aug 29.

Defining a therapeutic window for kinase inhibitors in leukemia to avoid neutropenia.

Author information

1
Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
2
Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
3
Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
4
Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
5
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
6
Monash Institute of Pharmaceutical Sciences, Melbourne, VIC, Australia.
7
Department of Clinical Microbiology and Immunology, Tel Aviv University, Tel Aviv, Israel.
8
School of Chemistry, Bio21, The University of Melbourne, Melbourne, VIC, Australia.
#
Contributed equally

Abstract

Neutropenia represents one of the major dose-limiting toxicities of many current cancer therapies. To circumvent the off-target effects of cytotoxic chemotherapeutics, kinase inhibitors are increasingly being used as an adjunct therapy to target leukemia. In this study, we conducted a screen of leukemic cell lines in parallel with primary neutrophils to identify kinase inhibitors with the capacity to induce apoptosis of myeloid and lymphoid cell lines whilst sparing primary mouse and human neutrophils. We have utilized a high-throughput live cell imaging platform to demonstrate that cytotoxic drugs have limited effects on neutrophil viability but are toxic to hematopoietic progenitor cells, with the exception of the topoisomerase I inhibitor SN-38. The parallel screening of kinase inhibitors revealed that mouse and human neutrophil viability is dependent on cyclin-dependent kinase (CDK) activity but surprisingly only partially dependent on PI3 kinase and JAK/STAT signaling, revealing dominant pathways contributing to neutrophil viability. Mcl-1 haploinsufficiency sensitized neutrophils to CDK inhibition, demonstrating that Mcl-1 is a direct target for CDK inhibitors. This study reveals a therapeutic window for the kinase inhibitors BEZ235, BMS-3, AZD7762, and (R)-BI-2536 to induce apoptosis of leukemia cell lines whilst maintaining immunocompetence and hemostasis.

KEYWORDS:

apoptosis; hematopoietic progenitor cells; kinase inhibitors; leukemia; neutropenia

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