Pharmacological and Protein Profiling Suggests Venetoclax (ABT-199) as Optimal Partner with Ibrutinib in Chronic Lymphocytic Leukemia.
Pharmacological and Protein Profiling Suggests Venetoclax (ABT-199) as Optimal Partner with Ibrutinib in Chronic Lymphocytic Leukemia.
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DOI：
10.1158/1078-0432.ccr-14-2809
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发表时间：
2015-08-15
期刊：
影响因子：
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通讯作者：
Gandhi V
中科院分区：
文献类型：
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作者：
Cervantes-Gomez F;Lamothe B;Woyach JA;Wierda WG;Keating MJ;Balakrishnan K;Gandhi V
Bruton‘s酪氨酸激酶(BTK)是B细胞受体途径中的一个关键酶，通过与激活域的共价结合而被伊布鲁替尼抑制。尽管伊布鲁替尼在慢性淋巴细胞白血病(CLL)的临床活动中取得了令人印象深刻的结果，但由于残留疾病，大多数患者只能实现部分缓解。我们对接受伊布鲁替尼治疗的患者残留的循环CLL细胞进行了药理学分析，以确定可以诱导这些淋巴细胞细胞死亡的最佳药物。在治疗开始前和治疗后(第2、4和12周)，从服用伊布鲁替尼的患者身上获取CLL细胞的体外系列样本。将这些细胞与PI3K抑制剂(idelalisib或IPI-145)、苯达莫司汀、额外的伊布鲁替尼或bcl2拮抗剂(ABT-737或ABT-199)孵育，并测量细胞死亡。体外研究补充了体外研究。免疫印迹法检测BTK信号通路和抗凋亡蛋白的表达。BCL-2拮抗剂，特别是ABT-199，在体外孵育过程中诱导高水平的细胞死亡。与体外数据一致的是，体外联合也产生了高度的细胞毒性。在伊布鲁替尼作用前和作用后2、4、12或36周获得的CLL细胞系列样本显示，BTK活性和对Abts的敏感性受到抑制。在CLL中过表达的三种bcl2家族抗凋亡蛋白中，经伊布鲁替尼干预后，mcl1和bclxl的表达水平降低，而ABT-199选择性地拮抗bcl2。我们的生物学和分子结果表明，ibrutinib和ABT-199联合治疗CLL应该在临床上进行测试。
Bruton’s tyrosine kinase (BTK) is a critical enzyme in the B-cell receptor pathway and is inhibited by ibrutinib due to covalent binding to the kinase domain. Though ibrutinib results in impressive clinical activity in chronic lymphocytic leukemia (CLL), most patients achieve only partial remission due to residual disease. We performed a pharmacologic profiling of residual circulating CLL cells from patients receiving ibrutinib to identify optimal agents that could induce cell death of these lymphocytes. Ex vivo serial samples of CLL cells from patients on ibrutinib were obtained prior and after (weeks 2, 4, and 12) the start of treatment. These cells were incubated with PI3K inhibitors (idelalisib or IPI-145), bendamustine, additional ibrutinib, or BCL-2 antagonists (ABT-737 or ABT-199) and cell death was measured. In vitro investigations complemented ex vivo studies. Immunoblots for BTK signaling pathway and antiapoptotic proteins were performed. The BCL-2 antagonists, especially ABT-199, induced high cell death during ex vivo incubations. In concert with the ex vivo data, in vitro combinations also resulted highly cytotoxicity. Serial samples of CLL cells obtained before and 2, 4, 12, or 36 weeks after the start of ibrutinib showed inhibition of BTK activity and sensitivity to ABTs. Among the three BCL-2 family anti-apoptotic proteins that are overexpressed in CLL, levels of MCL-1 and BCL-XL were decreased after ibrutinib while ABT-199 selectively antagonizes BCL-2. Our biological and molecular results suggest that ibrutinib and ABT-199 combination should be tested clinically against CLL.