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

Nature Communications
Richa BajpaiMala Shanmugam

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.

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Citations

Aug 15, 2020·Cell Death & Disease·Alba Roca-PortolesStephen W G Tait
Nov 4, 2020·Cell Death & Disease·Isha KapoorAlexandru Almasan
Jan 8, 2021·Frontiers in Oncology·Alessandro BarbatoAlessandra Romano
Dec 15, 2020·Journal of Hematology & Oncology·Arnold BolomskyJo Caers
Mar 20, 2021·Blood and Lymphatic Cancer : Targets and Therapy·Vikas A GuptaLawrence H Boise
Mar 21, 2021·Biochemical Pharmacology·Manon LernouxMarc Diederich
Oct 27, 2020·Journal of Medicinal Chemistry·Yibin XuNouri Neamati
May 6, 2021·International Journal of Molecular Sciences·Xiaonan ZhangMartina Bazzaro
Jun 3, 2021·Cancers·Mélody CaillotBrigitte Sola
Sep 26, 2021·Leukemia·Lucie de BeauchampG Vignir Helgason

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Methods Mentioned

BETA
RNAseq
coimmunoprecipitations
Protein Assay
electrophoresis
co-IP
FCS
Assay
transfection
flow cytometry
SeqFISH

Clinical Trials Mentioned

NCT02203773
NCT02287233
NCT01794520
NCT02899052
NCT02882321
NCT03291938
NCT02755597

Software Mentioned

XFe wave
FCS Express
GraphPad Prism
Gen5 Image +
SeqFISH
DESeq2
IHW R
Gen5
R package

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