Defining a therapeutic window for kinase inhibitors in leukemia to avoid neutropenia.
Defining a therapeutic window for kinase inhibitors in leukemia to avoid neutropenia.
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DOI：
10.18632/oncotarget.19678
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发表时间：
2017-08-29
期刊：
影响因子：
--
通讯作者：
Croker BA
中科院分区：
文献类型：
--
作者：
McArthur K;D'Cruz AA;Segal D;Lackovic K;Wilks AF;O'Donnell JA;Nowell CJ;Gerlic M;Huang DCS;Burns CJ;Croker BA
中性粒细胞增多症是目前许多癌症治疗的主要剂量限制性毒性之一。为了避免细胞毒性化疗药物的脱靶效应，激酶抑制剂越来越多地被用作靶向白血病的辅助治疗。在这项研究中，我们进行了白血病细胞系与原代中性粒细胞的平行筛选，以确定激酶抑制剂的能力，诱导骨髓和淋巴细胞系的凋亡，同时保留原代小鼠和人类中性粒细胞。我们已经利用高通量活细胞成像平台来证明细胞毒性药物对中性粒细胞活力的影响有限，但对造血祖细胞有毒性，拓扑异构酶I抑制剂SN-38除外。激酶抑制剂的平行筛选揭示了小鼠和人中性粒细胞活力依赖于细胞周期蛋白依赖性激酶（CDK）活性，但令人惊讶地仅部分依赖于PI 3激酶和JAK/STAT信号传导，揭示了有助于中性粒细胞活力的主要途径。Mcl-1单倍不足使中性粒细胞对CDK抑制敏感，表明Mcl-1是CDK抑制剂的直接靶点。这项研究揭示了激酶抑制剂BEZ 235、BMS-3、AZD 7762和（R）-BI-2536诱导白血病细胞系凋亡同时维持免疫活性和止血的治疗窗口。
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.
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影响因子：
5.7
作者：
Dai Y;Chen S;Kmieciak M;Zhou L;Lin H;Pei XY;Grant S
通讯作者：
Grant S
影响因子：
46.9
作者：
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--
DOI：
10.1073/pnas.0708800104
发表时间：
2007-12-18
影响因子：
11.1
作者：
Fedorov, Oleg;Marsden, Brian;Knapp, Stefan
通讯作者：
Knapp, Stefan
影响因子：
5
作者：
Elso, CM;Roberts, LJ;Handman, E
通讯作者：
Handman, E
影响因子：
--
作者：
Eltahla, Auda A.;Lackovic, Kurt;White, Peter A.
通讯作者：
White, Peter A.