文章：

MCL-1功能缺失使非霍奇金淋巴瘤细胞系对BCL-2选择性抑制剂venetoclax（ABT-199）敏感

Loss in MCL-1 function sensitizes non-Hodgkin’s lymphoma cell lines to the BCL-2-selective inhibitor venetoclax (ABT-199)

原文发布日期：2015-11-13

DOI: 10.1038/bcj.2015.88

类型: Original Article

开放获取: 是

英文摘要：

As a population, non-Hodgkin’s lymphoma (NHL) cell lines positive for the t(14;18) translocation and/or possessing elevated BCL2 copy number (CN; BCL2High) are exquisitely sensitive to navitoclax or the B-cell lymphoma protein-2 (BCL-2)-selective inhibitor venetoclax. Despite this, some BCL2High cell lines remain resistant to either agent. Here we show that the MCL-1-specific inhibitor A-1210477 sensitizes these cell lines to navitoclax. Chemical segregation of this synergy with the BCL-2-selective inhibitor venetoclax or BCL-XL-selective inhibitor A-1155463 indicated that MCL-1 and BCL-2 are the two key anti-apoptotic targets for sensitization. Similarly, the CDK inhibitor flavopiridol downregulated MCL-1 expression and synergized with venetoclax in BCL2High NHL cell lines to a similar extent as A-1210477. A-1210477 also synergized with navitoclax in the majority of BCL2Low NHL cell lines. However, chemical segregation with venetoclax or A-1155463 revealed that synergy was driven by BCL-XL inhibition in this population. Collectively these data emphasize that BCL2 status is predictive of venetoclax potency in NHL not only as a single agent, but also in the adjuvant setting with anti-tumorigenic agents that inhibit MCL-1 function. These studies also potentially identify a patient population (BCL2Low) that could benefit from BCL-XL (navitoclax)-driven combination therapy.

摘要翻译： 

作为一类群体，携带t(14;18)易位和/或BCL2拷贝数增高（BCL2High）的非霍奇金淋巴瘤（NHL）细胞系对navitoclax或选择性BCL-2抑制剂venetoclax具有高度敏感性。尽管如此，部分BCL2High细胞系仍对这些药物存在耐药性。本研究表明MCL-1特异性抑制剂A-1210477能增强此类细胞系对navitoclax的敏感性。通过BCL-2选择性抑制剂venetoclax与BCL-XL选择性抑制剂A-1155463的化学分离实验，确认MCL-1和BCL-2是实现增敏效应的两个关键抗凋亡靶点。类似地，CDK抑制剂flavopiridol通过下调MCL-1表达，在BCL2High NHL细胞系中与venetoclax产生的协同效应与A-1210477相当。在大多数BCL2Low NHL细胞系中，A-1210477也能与navitoclax产生协同作用，但通过venetoclax或A-1155463的化学分离实验显示，该协同效应主要由BCL-XL抑制驱动。这些数据共同表明，BCL2状态不仅能预测venetoclax单药在NHL中的疗效，还能预测其与抑制MCL-1功能的抗肿瘤药物联合使用的疗效。本研究还可能识别出可从BCL-XL（navitoclax）驱动联合疗法中获益的患者群体（BCL2Low）。

原文链接：

Loss in MCL-1 function sensitizes non-Hodgkin’s lymphoma cell lines to the BCL-2-selective inhibitor venetoclax (ABT-199)