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; Mala Shanmugam

doi:10.1038/s41467-020-15051-z

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, Mala Shanmugam

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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.

Original language	English (US)
Article number	1228
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-15051-z
State	Published - Dec 1 2020

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Bajpai, R., Sharma, A., Achreja, A., Edgar, C. L., Wei, C., Siddiqa, A. A., Gupta, V. A., Matulis, S. M., McBrayer, S. K., Mittal, A., Rupji, M., Barwick, B. G., Lonial, S., Nooka, A. K., Boise, L. H., Nagrath, D., & Shanmugam, M. (2020). Electron transport chain activity is a predictor and target for venetoclax sensitivity in multiple myeloma. Nature communications, 11(1), Article 1228. https://doi.org/10.1038/s41467-020-15051-z

Bajpai, R, Sharma, A, Achreja, A, Edgar, CL, Wei, C, Siddiqa, AA, Gupta, VA, Matulis, SM, McBrayer, SK, Mittal, A, Rupji, M, Barwick, BG, Lonial, S, Nooka, AK, Boise, LH, Nagrath, D & Shanmugam, M 2020, 'Electron transport chain activity is a predictor and target for venetoclax sensitivity in multiple myeloma', Nature communications, vol. 11, no. 1, 1228. https://doi.org/10.1038/s41467-020-15051-z

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title = "Electron transport chain activity is a predictor and target for venetoclax sensitivity in multiple myeloma",

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 {\textquoteleft}primed{\textquoteright} 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.",

author = "Richa Bajpai and Aditi Sharma and Abhinav Achreja and Edgar, {Claudia L.} and Changyong Wei and Siddiqa, {Arusha A.} and Gupta, {Vikas A.} and Matulis, {Shannon M.} and McBrayer, {Samuel K.} and Anjali Mittal and Manali Rupji and Barwick, {Benjamin G.} and Sagar Lonial and Nooka, {Ajay K.} and Boise, {Lawrence H.} and Deepak Nagrath and Mala Shanmugam",

note = "Funding Information: We would like to thank Anthea Hammond, Ph.D., Emory University for editorial assistance. 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. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

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doi = "10.1038/s41467-020-15051-z",

language = "English (US)",

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T1 - Electron transport chain activity is a predictor and target for venetoclax sensitivity in multiple myeloma

AU - Bajpai, Richa

AU - Sharma, Aditi

AU - Achreja, Abhinav

AU - Edgar, Claudia L.

AU - Wei, Changyong

AU - Siddiqa, Arusha A.

AU - Gupta, Vikas A.

AU - Matulis, Shannon M.

AU - McBrayer, Samuel K.

AU - Mittal, Anjali

AU - Rupji, Manali

AU - Barwick, Benjamin G.

AU - Lonial, Sagar

AU - Nooka, Ajay K.

AU - Boise, Lawrence H.

AU - Nagrath, Deepak

AU - Shanmugam, Mala

N1 - Funding Information: We would like to thank Anthea Hammond, Ph.D., Emory University for editorial assistance. 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. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

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

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