Journal Article

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

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

2020

Overview

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. Venetoclax monotherapy is effective in 40% of t(11:14) positive multiple myeloma (MM). Here, the authors show that electron transport chain complex I (CI) and complex II (CII) activity predict MM sensitivity to venetoclax, and inhibition of CI with IACS-010759 or CII with TTFA increase sensitivity.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/109 / 13/31 / 13/51 / 42/41 / 42/44 / 42/89 / 631/337 / 631/45/607 / 631/67/1990/804 / 631/80 / 692/4028/67/1059 / 82/29 / 96/2 / Bcl-2 protein / BIM protein / Bioavailability / Biomarkers / Bridged Bicyclo Compounds, Heterocyclic - pharmacology / Bridged Bicyclo Compounds, Heterocyclic - therapeutic use / Cell Line, Tumor / Chromosomes, Human, Pair 11 - genetics / Chromosomes, Human, Pair 14 - genetics / Clinical trials / Drug Resistance, Neoplasm / Electron transport / Electron Transport - drug effects / Electron transport chain / Electron Transport Complex I - antagonists & inhibitors / Electron Transport Complex I - metabolism / Electron Transport Complex II - antagonists & inhibitors / Electron Transport Complex II - metabolism / Gene Knockdown Techniques / Humanities and Social Sciences / Humans / Membrane Proteins - genetics / Mitochondria / Mitochondria - drug effects / Mitochondria - metabolism / multidisciplinary / Multiple myeloma / Multiple Myeloma - drug therapy / Multiple Myeloma - genetics / Multiple Myeloma - pathology / Mutants / Mutation / Oxidation-Reduction - drug effects / Patient Selection / Prognosis / Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors / Proto-Oncogene Proteins c-bcl-2 - metabolism / Reductase / Reductases / Science / Science (multidisciplinary) / Sensitivity / Sulfonamides - pharmacology / Sulfonamides - therapeutic use / Thenoyltrifluoroacetone - pharmacology / Translocation / Translocation, Genetic / Ubiquinone