PMID- 37702657
OWN - NLM
STAT- MEDLINE
DCOM- 20231204
LR  - 20240209
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 83
IP  - 23
DP  - 2023 Dec 1
TI  - CK1delta and CK1epsilon Signaling Sustains Mitochondrial Metabolism and Cell Survival in 
      Multiple Myeloma.
PG  - 3901-3919
LID - 10.1158/0008-5472.CAN-22-2350 [doi]
AB  - Multiple myeloma remains an incurable malignancy due to acquisition of intrinsic 
      programs that drive therapy resistance. Here we report that casein kinase-1delta 
      (CK1delta) and CK1epsilon are therapeutic targets in multiple myeloma that are necessary to 
      sustain mitochondrial metabolism. Specifically, the dual CK1delta/CK1epsilon inhibitor 
      SR-3029 had potent in vivo and ex vivo anti-multiple myeloma activity, including 
      against primary multiple myeloma patient specimens. RNA sequencing (RNA-seq) and 
      metabolic analyses revealed inhibiting CK1delta/CK1epsilon disables multiple myeloma 
      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 multiple myeloma patient 
      specimens to SR-3029 correlated with elevated expression of mitochondrial genes, 
      and RNA-seq from 687 multiple myeloma patient samples revealed that increased 
      CSNK1D, CSNK1E, and OxPhos genes correlate with disease progression and inferior 
      outcomes. Thus, increases in mitochondrial metabolism are a hallmark of multiple 
      myeloma progression that can be disabled by targeting CK1delta/CK1epsilon. SIGNIFICANCE: 
      CK1delta and CK1epsilon are attractive therapeutic targets in multiple myeloma whose 
      expression increases with disease progression and connote poor outcomes, and that 
      are necessary to sustain expression of genes directing OxPhos.
CI  - (c)2023 The Authors; Published by the American Association for Cancer Research.
FAU - Burger, Karen L
AU  - Burger KL
AUID- ORCID: 0000-0002-3805-9580
AD  - Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, 
      Tampa, Florida.
FAU - Fernandez, Mario R
AU  - Fernandez MR
AUID- ORCID: 0000-0002-2017-9576
AD  - Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, 
      Tampa, Florida.
FAU - Meads, Mark B
AU  - Meads MB
AUID- ORCID: 0009-0008-0259-1875
AD  - Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research 
      Institute, Tampa, Florida.
FAU - Sudalagunta, Praneeth
AU  - Sudalagunta P
AUID- ORCID: 0000-0003-1283-9332
AD  - Department of Metabolism & Physiology, H. Lee Moffitt Cancer Center & Research 
      Institute, Tampa, Florida.
FAU - Oliveira, Paula S
AU  - Oliveira PS
AUID- ORCID: 0009-0007-2128-7302
AD  - Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research 
      Institute, Tampa, Florida.
FAU - Renatino Canevarolo, Rafael
AU  - Renatino Canevarolo R
AUID- ORCID: 0000-0002-8722-8512
AD  - Department of Metabolism & Physiology, H. Lee Moffitt Cancer Center & Research 
      Institute, Tampa, Florida.
FAU - Alugubelli, Raghunandan Reddy
AU  - Alugubelli RR
AUID- ORCID: 0000-0002-4314-1204
AD  - Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research 
      Institute, Tampa, Florida.
FAU - Tungsevik, Alexandre
AU  - Tungsevik A
AUID- ORCID: 0009-0003-5208-5886
AD  - Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research 
      Institute, Tampa, Florida.
FAU - De Avila, Gabe
AU  - De Avila G
AUID- ORCID: 0000-0003-3826-862X
AD  - Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research 
      Institute, Tampa, Florida.
FAU - Silva, Maria
AU  - Silva M
AUID- ORCID: 0009-0008-6787-6695
AD  - Department of Metabolism & Physiology, H. Lee Moffitt Cancer Center & Research 
      Institute, Tampa, Florida.
FAU - Graeter, Allison I
AU  - Graeter AI
AUID- ORCID: 0000-0001-6782-0298
AD  - Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research 
      Institute, Tampa, Florida.
FAU - Dai, Hongyue A
AU  - Dai HA
AUID- ORCID: 0000-0002-6609-9141
AD  - Informatics Division, M2Gen(R), Tampa, Florida.
FAU - Vincelette, Nicole D
AU  - Vincelette ND
AUID- ORCID: 0000-0001-7627-6781
AD  - Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research 
      Institute, Tampa, Florida.
FAU - Prabhu, Antony
AU  - Prabhu A
AUID- ORCID: 0000-0003-2401-0118
AD  - Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, 
      Tampa, Florida.
FAU - Magaletti, Dario
AU  - Magaletti D
AUID- ORCID: 0009-0005-2371-9290
AD  - Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, 
      Tampa, Florida.
AD  - Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research 
      Institute, Tampa, Florida.
FAU - Yang, Chunying
AU  - Yang C
AUID- ORCID: 0000-0001-8188-0860
AD  - Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, 
      Tampa, Florida.
FAU - Li, Weimin
AU  - Li W
AUID- ORCID: 0000-0001-7815-0859
AD  - Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, 
      Tampa, Florida.
FAU - Kulkarni, Amit
AU  - Kulkarni A
AUID- ORCID: 0009-0000-4624-4789
AD  - Informatics Division, M2Gen(R), Tampa, Florida.
FAU - Hampton, Oliver
AU  - Hampton O
AUID- ORCID: 0000-0001-9164-1070
AD  - Informatics Division, M2Gen(R), Tampa, Florida.
FAU - Koomen, John M
AU  - Koomen JM
AUID- ORCID: 0000-0002-3818-1762
AD  - Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research 
      Institute, Tampa, Florida.
FAU - Roush, William R
AU  - Roush WR
AUID- ORCID: 0000-0001-9785-5897
AD  - Department of Chemistry, Scripps Research, Jupiter, Florida.
FAU - Monastyrskyi, Andrii
AU  - Monastyrskyi A
AUID- ORCID: 0000-0002-1145-1822
AD  - Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, 
      Tampa, Florida.
FAU - Berglund, Anders E
AU  - Berglund AE
AUID- ORCID: 0000-0002-0393-3530
AD  - Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & 
      Research Institute, Tampa, Florida.
FAU - Silva, Ariosto S
AU  - Silva AS
AUID- ORCID: 0000-0003-3237-9986
AD  - Department of Metabolism & Physiology, H. Lee Moffitt Cancer Center & Research 
      Institute, Tampa, Florida.
FAU - Cleveland, John L
AU  - Cleveland JL
AUID- ORCID: 0000-0002-7561-9065
AD  - Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, 
      Tampa, Florida.
FAU - Shain, Kenneth H
AU  - Shain KH
AUID- ORCID: 0000-0003-4178-8888
AD  - Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, 
      Tampa, Florida.
AD  - Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research 
      Institute, Tampa, Florida.
LA  - eng
GR  - F32 CA203217/CA/NCI NIH HHS/United States
GR  - P30 CA076292/CA/NCI NIH HHS/United States
GR  - U54 CA193489/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - EC 2.7.11.1 (Casein Kinase Idelta)
SB  - IM
MH  - Humans
MH  - *Casein Kinase Idelta/genetics/metabolism
MH  - *Multiple Myeloma/genetics
MH  - Cell Survival
MH  - Phosphorylation
MH  - Disease Progression
PMC - PMC10690099
EDAT- 2023/09/13 12:42
MHDA- 2023/12/04 12:42
PMCR- 2023/12/01
CRDT- 2023/09/13 10:33
PHST- 2022/07/24 00:00 [received]
PHST- 2023/06/09 00:00 [revised]
PHST- 2023/09/08 00:00 [accepted]
PHST- 2023/12/04 12:42 [medline]
PHST- 2023/09/13 12:42 [pubmed]
PHST- 2023/09/13 10:33 [entrez]
PHST- 2023/12/01 00:00 [pmc-release]
AID - 729039 [pii]
AID - CAN-22-2350 [pii]
AID - 10.1158/0008-5472.CAN-22-2350 [doi]
PST - ppublish
SO  - Cancer Res. 2023 Dec 1;83(23):3901-3919. doi: 10.1158/0008-5472.CAN-22-2350.