Electron transport chain activity is a predictor and target for venetoclax sensitivity in multiple myeloma
| العنوان: | Electron transport chain activity is a predictor and target for venetoclax sensitivity in multiple myeloma |
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| المؤلفون: | Benjamin G. Barwick, Arusha A. Siddiqa, Anjali Mittal, Samuel K. McBrayer, Changyong Wei, Mala Shanmugam, Deepak Nagrath, Aditi Sharma, Ajay K. Nooka, Richa Bajpai, Abhinav Achreja, Claudia L. Edgar, Vikas Gupta, Sagar Lonial, Manali Rupji, Shannon M. Matulis, Lawrence H. Boise |
| المصدر: | Nature Communications, Vol 11, Iss 1, Pp 1-16 (2020) Nature Communications |
| بيانات النشر: | Nature Publishing Group, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. |
| اللغة: | English |
| تدمد: | 2041-1723 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3f5d9e6fffd24eed6ab538cbd5ccac4bTest http://link.springer.com/article/10.1038/s41467-020-15051-zTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....3f5d9e6fffd24eed6ab538cbd5ccac4b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20411723 |
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