High-content screening identifies kinase inhibitors that overcome venetoclax resistance in activated CLL cells
High-content screening identifies kinase inhibitors that overcome venetoclax resistance in activated CLL cells
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DOI：
10.1182/blood-2015-12-687814
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发表时间：
2016-08-18
期刊：
影响因子：
20.3
通讯作者：
Andrews, David W.
中科院分区：
文献类型：
--
作者：
Oppermann, Sina;Ylanko, Jarkko;Andrews, David W.
新的药物，如Bcl-2抑制剂venotclax(ABT-199)正在改变慢性淋巴细胞白血病(CLL)的治疗模式，但仍然存在重要问题。尽管一些患者对万乃馨作为单一药物表现出深刻而持久的反应，但另一些患者存在介导疾病复发的耐药白血病细胞亚群。对万乃馨耐药的一个假说是，在增殖中心遇到的激酶介导的生存信号可能是个别患者独一无二的。建立了一个体外微环境模型，将原代CLL细胞合并到基于自动高含量显微镜的激酶抑制剂(KIS)筛查中，以确定可能以个性化方式改善静脉滴注治疗的药物。患者间有明显的可变性，KIS是有效的；然而，舒尼替尼被认为是临床上最常见的有效克服万乃洛耐药的KI。对潜在机制的研究表明，万乃馨抗性可能是由上调抗凋亡基因Bclxl、Mcl-1和A1的微环境信号诱导的，而Sunitinib比ibrutinib或idelalisib更能有效地抵消这些信号。尽管患者特有的药物反应很常见，但对于许多患者来说，与舒尼替尼联合治疗可能会显著提高维奈替克的疗效。
Novel agents such as the Bcl-2 inhibitor venetoclax (ABT-199) are changing treatment paradigms for chronic lymphocytic leukemia (CLL) but important problems remain. Although some patients exhibit deep and durable responses to venetoclax as a single agent, other patients harbor subpopulations of resistant leukemia cells that mediate disease recurrence. One hypothesis for the origin of resistance to venetoclax is by kinase-mediated survival signals encountered in proliferation centers that may be unique for individual patients. An in vitro microenvironment model was developed with primary CLL cells that could be incorporated into an automated high-content microscopy-based screen of kinase inhibitors (KIs) to identify agents that may improve venetoclax therapy in a personalized manner. Marked interpatient variability was noted for which KIs were effective; nevertheless, sunitinib was identified as the most common clinically available KI effective in overcoming venetoclax resistance. Examination of the underlying mechanisms indicated that venetoclax resistance may be induced by microenvironmental signals that upregulate antiapoptotic Bcl-xl, Mcl-1, and A1, which can be counteracted more efficiently by sunitinib than by ibrutinib or idelalisib. Although patient-specific drug responses are common, for many patients, combination therapy with sunitinib may significantly improve the therapeutic efficacy of venetoclax.