Defining a therapeutic window for kinase inhibitors in leukemia to avoid neutropenia
Details
Publication Year 2017-08-29, Volume 8, Issue #35, Page 57948-57963
Journal Title
Oncotarget
Publication Type
Journal Article
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.
Publisher
Impact Journals
WEHI Research Division(s)
Systems Biology And Personalised Medicine; Chemical Biology; Cancer And Haematology
PubMed ID
28938529
Open Access at Publisher's Site
https://doi.org/10.18632/oncotarget.19678
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2017-10-16 02:00:07
Last Modified: 2017-10-16 04:49:40
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