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期刊名称: Blood Cancer Journal
Volume:5    Page:e368-e368
ISSN:2044-5385

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

作者: Phillips D.C Xiao Y Lam L.T Litvinovich E Roberts-Rapp L
DOI:10.1038/bcj.2015.88

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页码: e368-e368
被引频次: 36
出版者: NATURE PUBLISHING GROUP,Springer Nature B.V
期刊名称: Blood Cancer Journal
ISSN: 2044-5385
语言: English
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; BCL2(High)) are exquisitely sensitive to navitoclax or the B-cell lymphoma protein-2 (BCL-2)-selective inhibitor venetoclax. Despite this, some BCL2(High) 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-X-L-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 BCL2(High) NHL cell lines to a similar extent as A-1210477. A-1210477 also synergized with navitoclax in the majority of BCL2(Low) NHL cell lines. However, chemical segregation with venetoclax or A-1155463 revealed that synergy was driven by BCL-X-L 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 (BCL2(Low)) that could benefit from BCL-X-L (navitoclax)-driven combination therapy.
相关主题: MULTIPLE-MYELOMA, SURVIVAL, BCL-X-L, ONCOLOGY, IN-VIVO, HIGH-AFFINITY, C-MYC, CHRONIC LYMPHOCYTIC-LEUKEMIA, SMALL-MOLECULE INHIBITOR, NAVITOCLAX ABT-263, FLAVOPIRIDOL, Index Medicus,

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