CK1δ/CK1ε Signaling Sustains Mitochondrial Metabolism and Cell Survival in Multiple Myeloma

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.