多发性骨髓瘤（MM）由于获得推动治疗耐药性的内在机制而仍然无法治愈。在这里，我们报告了酪蛋白激酶-1δ（CK1δ）和CK1ε在MM中是治疗靶点，对维持线粒体代谢至关重要。具体而言，双重CK1δ/CK1ε抑制剂SR-3029在体内和体外显示出强效的抗MM活性，包括对原发性MM患者标本的活性。RNA测序（RNA-seq）和代谢分析揭示，抑制CK1δ/CK1ε可通过抑制参与氧化磷酸化（OxPhos）的基因、减少柠檬酸循环中间体和抑制电子传递链的I和IV复合物来阻断MM的代谢。最后，MM患者标本对SR-3029的敏感性与线粒体基因的高表达相关，而来自687例MM患者样本的RNA测序结果显示，CSNK1D、CSNK1E和OxPhos基因的增加与疾病进展和不良预后相关。因此，线粒体代谢的增加是MM进展的特征，可以通过靶向CK1δ/CK1ε来阻断。

Multiple myeloma (MM) remains an incurable malignancy due to acquisition of intrinsic programs that drive therapy resistance. Here we report that casein kinase-1δ (CK1δ) and CK1ε are therapeutic targets in MM that are necessary to sustain mitochondrial metabolism. Specifically, the dual CK1δ/CK1ε inhibitor SR-3029 had potent in vivo and ex vivo anti-MM activity, including against primary MM patient specimens. RNA sequencing (RNA-seq) and metabolic analyses revealed inhibiting CK1δ/CK1ε disables MM metabolism by suppressing genes involved in oxidative phosphorylation (OxPhos), reducing citric acid cycle intermediates, and suppressing Complexes I and IV of the electron transport chain. Finally, sensitivity of MM patient specimens to SR-3029 correlated with elevated expression of mitochondrial genes, and RNA-seq from 687 MM patient samples revealed that increased CSNK1D, CSNK1E, and OxPhos genes correlates with disease progression and inferior outcomes. Thus, increases in mitochondrial metabolism are a hallmark of MM progression that can be disabled by targeting CK1δ/CK1ε.