Department of Hematology and Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta, GA, USA.
Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
Nat Commun. 2020 Mar 6;11(1):1228. doi: 10.1038/s41467-020-15051-z.
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.
BCL-2 拮抗剂 venetoclax 对多发性骨髓瘤（MM）患者中出现 11;14 易位的患者非常有效，其机制尚不清楚。在评估 t(11;14)和非 t(11;14)MM 的细胞能量学和代谢时，我们确定 venetoclax 敏感的骨髓瘤具有降低的线粒体呼吸作用。与此一致的是，低电子传递链（ETC）复合物 I 和复合物 II 的活性与 venetoclax 的敏感性相关。使用 IACS-010759（一种正在临床试验中的口服生物可利用的复合物 I 抑制剂）抑制复合物 I，以及使用 thenoyltrifluoroacetone（TTFA）或引入 SDHC R72C 突变体抑制复合物 II 的琥珀酸辅酶 Q 还原酶（SQR）活性，均可使耐药 MM 独立地对 venetoclax 敏感。我们证明，ETC 抑制通过 ATF4-BIM/NOXA 轴增加 BCL-2 的依赖性和“启动”状态。此外，无论 t(11;14)状态如何，患者样本中的 SQR 活性都与 venetoclax 的敏感性相关。以功能生物标志物指导的方式使用 SQR 活性可能会更好地选择对 venetoclax 治疗有反应的 MM 患者。
