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Author Notes:

Correspondence: Mala Shanmugam, mala.shan@emory.edu

R.B., A.S. and M.S. conceived and designed the research. R.B., A.S. and C.L.E. performed all experimentation with assistance from C.W., A.A.S. and S.K.M. Metabolome and bioinformatic analyses were performed by A.A. and A.M. under the supervision of D.N. S.M.M. and V.A.G. assisted with patient sample purification and performed NOXA gene editing.

A.K.N., S.L. oversaw myeloma patient sample collection. Statistical evaluation was performed by M.R. and B.G.B. L.H.B., V.A.G., B.G.B., A.K.N., S.K.M., A.A.S., C.L.E., A.A., A.M. and D.N. provided helpful critique. R.B., A.S. and M.S. created Fig. ​Fig.7e.7e. R.B., A.S. and M.S. wrote the manuscript.

We would like to thank Anthea Hammond, Ph.D., Emory University for editorial assistance.

Disclosures: S.K.M. is a consultant for Agios Pharmaceuticals; L.H.B. is a consultant for Abbvie, consultant for Genentech and has research funding and is a consultant for Astra Zeneca.

A.K.N. is consultant with honoraria from Janssen, GSK, Celgene, Amgen, Takeda, Spectrum, BMS, Adaptive and research funding from Janssen, GSK, Celgene, Amgen, Takeda, BMS; S.L. is a consultant and receives honoraria for Millennium, Onyx Pharmaceuticals, Novartis, BMS, Janssen, and Celgene and received honorarium from Celgene, Takeda, BMS, GSK, Novartis, Amgen, Merck, and Janssen.

All other authors declare no competing interests.

Subjects:

Research Funding:

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:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • Amino acid metabolism
  • Cell death
  • Mitochondrial complex
  • Clinical response
  • BCL-2 inhibition
  • BH3 domain
  • ER stress
  • Protein
  • Resistance
  • Apoptosis

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

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Journal Title:

Nature Communications

Volume:

Volume 11, Number 1

Publisher:

, Pages 1228-1228

Type of Work:

Article | Final Publisher PDF

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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© The Author(s) 2020.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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