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

Author

Listed:
  • Richa Bajpai

    (Emory University)

  • Aditi Sharma

    (Emory University)

  • Abhinav Achreja

    (University of Michigan
    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
    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
    University of Michigan
    University of Michigan)

  • Mala Shanmugam

    (Emory University)

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.

Suggested Citation

  • 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 & Benjami, 2020. "Electron transport chain activity is a predictor and target for venetoclax sensitivity in multiple myeloma," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15051-z
    DOI: 10.1038/s41467-020-15051-z
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    Cited by:

    1. Cameron S. Fraser & Johan K. E. Spetz & Xingping Qin & Adam Presser & Jonathan Choiniere & Chendi Li & Stacey Yu & Frances Blevins & Aaron N. Hata & Jeffrey W. Miller & Gary A. Bradshaw & Marian Kaloc, 2022. "Exploiting endogenous and therapy-induced apoptotic vulnerabilities in immunoglobulin light chain amyloidosis with BH3 mimetics," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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