Electron transport chain activity is a predictor and target for venetoclax sensitivity in multiple myeloma

被引：68
|
作者：
Bajpai, Richa [1 ]
Sharma, Aditi [1 ]
Achreja, Abhinav [2 ,3 ]
Edgar, Claudia L. [1 ]
Wei, Changyong [1 ]
Siddiqa, Arusha A. [1 ]
Gupta, Vikas A. [1 ]
Matulis, Shannon M. [1 ]
McBrayer, Samuel K. [4 ]
Mittal, Anjali [3 ,5 ]
Rupji, Manali [6 ]
Barwick, Benjamin G. [1 ]
Lonial, Sagar [1 ]
Nooka, Ajay K. [1 ]
Boise, Lawrence H. [1 ]
Nagrath, Deepak [2 ,3 ,5 ]
Shanmugam, Mala [1 ]
机构：
[1] Emory Univ, Sch Med, Winship Canc Inst, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA
[2] Univ Michigan, Dept Biomed Engn, Ann Arbor, MI 48109 USA
[3] Univ Michigan, Biointerfaces Inst, Ann Arbor, MI 48109 USA
[4] Univ Texas Southwestern Med Ctr Dallas, Childrens Med Ctr Res Inst, Dallas, TX 75390 USA
[5] Univ Michigan, Dept Chem Engn, Ann Arbor, MI 48109 USA
[6] Emory Univ, Winship Canc Inst, Dept Biostat & Bioinformat Shared Resource, Atlanta, GA 30322 USA
来源：
NATURE COMMUNICATIONS | 2020年 / 11卷 / 01期
关键词：
AMINO-ACID-METABOLISM; CELL-DEATH; MITOCHONDRIAL COMPLEX; CLINICAL-RESPONSE; BCL-2; INHIBITION; BH3; DOMAIN; ER STRESS; PROTEIN; RESISTANCE; APOPTOSIS;
D O I：
10.1038/s41467-020-15051-z
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
The BCL-2 antagonist venetoclax is highly effective in multiple myeloma (MM) patients exhibiting the 11;14 translocation, the mechanistic basis of which is unknown. In evaluating cellular energetics and metabolism of t(11;14) and non-t(11;14) MM, we determine that venetoclax-sensitive myeloma has reduced mitochondrial respiration. Consistent with this, low electron transport chain (ETC) Complex I and Complex II activities correlate with venetoclax sensitivity. Inhibition of Complex I, using IACS-010759, an orally bioavailable Complex I inhibitor in clinical trials, as well as succinate ubiquinone reductase (SQR) activity of Complex II, using thenoyltrifluoroacetone (TTFA) or introduction of SDHC R72C mutant, independently sensitize resistant MM to venetoclax. We demonstrate that ETC inhibition increases BCL-2 dependence and the `primed' state via the ATF4-BIM/NOXA axis. Further, SQR activity correlates with venetoclax sensitivity in patient samples irrespective of t(11;14) status. Use of SQR activity in a functional-biomarker informed manner may better select for MM patients responsive to venetoclax therapy.
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页数：16
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