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

Richa Bajpai, Aditi Sharma, Abhinav Achreja, Claudia L. Edgar, Changyong Wei, Arusha A. Siddiqa, Vikas A. Gupta, Shannon M. Matulis, Samuel K. McBrayer, Anjali Mittal, Manali Rupji, Benjamin G. Barwick, Sagar Lonial, Ajay K. Nooka, Lawrence H. Boise, Deepak Nagrath and Mala Shanmugam ()
Additional contact information
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 M. Matulis: Emory University
Samuel K. McBrayer: University of Texas Southwestern Medical Center
Anjali Mittal: University of Michigan
Manali Rupji: Emory University
Benjamin G. Barwick: Emory University
Sagar Lonial: Emory University
Ajay K. Nooka: Emory University
Lawrence H. Boise: Emory University
Deepak Nagrath: University of Michigan
Mala Shanmugam: Emory University

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15051-z

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