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Electron transport chain activity is a predictor and target for venetoclax sensitivity in multiple myeloma
- Source :
- Nature Communications, Vol 11, Iss 1, Pp 1-16 (2020), Nature Communications
- Publication Year :
- 2020
- Publisher :
- Nature Publishing Group, 2020.
-
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.<br />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.
- Subjects :
- 0301 basic medicine
Cancer therapy
Molecular biology
Mutant
General Physics and Astronomy
Chromosomal translocation
Myeloma
Pharmacology
Translocation, Genetic
chemistry.chemical_compound
0302 clinical medicine
lcsh:Science
Multiple myeloma
Thenoyltrifluoroacetone
Sulfonamides
Multidisciplinary
Chemistry
Electron Transport Complex II
Prognosis
3. Good health
Mitochondria
Enzymes
Proto-Oncogene Proteins c-bcl-2
030220 oncology & carcinogenesis
Gene Knockdown Techniques
Multiple Myeloma
Oxidation-Reduction
musculoskeletal diseases
Cell biology
Science
General Biochemistry, Genetics and Molecular Biology
Article
Electron Transport
03 medical and health sciences
Cell Line, Tumor
medicine
Humans
Chromosomes, Human, Pair 14
Electron Transport Complex I
Venetoclax
Chromosomes, Human, Pair 11
Patient Selection
Antagonist
Membrane Proteins
General Chemistry
Metabolism
medicine.disease
Bridged Bicyclo Compounds, Heterocyclic
030104 developmental biology
Cell culture
Drug Resistance, Neoplasm
Mutation
lcsh:Q
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 11
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....3f5d9e6fffd24eed6ab538cbd5ccac4b