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

• Type of Material: Article
• Authors: Richa Bajpai, Emory University; Aditi Sharma, Emory University; Abhinav Achreja, University of Michigan; Claudia L. Edgar, Emory University; Changyong Wei, Emory University; Arusha A. Siddiqa, Emory University; Vikas A. Gupta, Emory University; Shannon Matulis, Emory University; Samuel K. McBrayer, University of Texas Dallas; Anjali Mittal, University of Michigan; Manali Rupji, Emory University; Benjamin Barwick, Emory University; Sagar Lonial, Emory University; Ajay Nooka, Emory University; Lawrence Boise, Emory University; Deepak Nagrath, University of Michigan; Malathy Shanmugam, Emory University
• Language: English
• Date: 2020-03-06
• Publisher: Nature Research
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2020.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-020-15051-z
• Title of Journal or Parent Work: Nature Communications
• Volume: 11
• Issue: 1
• Start Page: 1228
• End Page: 1228
• Grant/Funding Information: This study was supported in part by NIH/NCI R01 CA208328 to M.S. and Leukemia Lymphoma Society TRP Award #6573-19 to M.S.; Research reported in this publication was supported in part by the Biostatistics and Bioinformatics Shared Resource of Winship Cancer Institute of Emory University and NIH/NCI under award number P30CA138292 and the Integrated Cellular Imaging Microscopy Core of the Winship Cancer Institute of Emory University and NIH/NCI under award number, 2P30CA138292-04.
• Keywords: Resistance; Mitochondrial complex; ER stress; BH3 domain; Protein; Science & Technology - Other Topics; Amino acid metabolism; Science & Technology; BCL-2 inhibition; Cell death; Clinical response; Multidisciplinary Sciences; Apoptosis
• Research Categories: Biology, Cell; Biology, Biostatistics; Engineering, Biomedical; Health Sciences, Oncology

Abstract

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.