Defining a therapeutic window for kinase inhibitors in leukemia to avoid neutropenia
D'Cruz, Akshay A.
Wilks, Andrew F.
O'Donnell, Joanne A.
Nowell, Cameron J.
Huang, David C. S.
Burns, Christopher J.
Croker, Ben A.
UMass Chan AffiliationsDepartment of Molecular, Cell and Cancer Biology
Document TypeJournal Article
hematopoietic progenitor cells
Hemic and Lymphatic Diseases
MetadataShow full item record
AbstractNeutropenia 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.
SourceOncotarget. 2017 Jul 28;8(35):57948-57963. doi: 10.18632/oncotarget.19678. eCollection 2017 Aug 29. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/40388
RightsCopyright: McArthur et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Except where otherwise noted, this item's license is described as Copyright: McArthur et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.