PMID- 36400430
OWN - NLM
STAT- MEDLINE
DCOM- 20230213
LR  - 20230303
IS  - 1878-0261 (Electronic)
IS  - 1574-7891 (Print)
IS  - 1574-7891 (Linking)
VI  - 17
IP  - 2
DP  - 2023 Feb
TI  - SMG1, a nonsense-mediated mRNA decay (NMD) regulator, as a candidate therapeutic 
      target in multiple myeloma.
PG  - 284-297
LID - 10.1002/1878-0261.13343 [doi]
AB  - Early data suggested that CC-115, a clinical molecule, already known to inhibit 
      the mammalian target of rapamycin kinase (TORK) and DNA-dependent protein kinase 
      (DNA-PK) may have additional targets beyond TORK and DNA-PK. Therefore, we aimed 
      to identify such target(s) and investigate a potential therapeutic applicability. 
      Functional profiling of 141 cancer cell lines revealed inhibition of kinase 
      suppressor of morphogenesis in genitalia 1 (SMG1), a key regulator of the RNA 
      degradation mechanism nonsense-mediated mRNA decay (NMD), as an additional target 
      of CC-115. CC-115 treatment showed a dose-dependent increase of SMG1-mediated NMD 
      transcripts. A subset of cell lines, including multiple myeloma (MM) cell lines 
      sensitive to the endoplasmic reticulum stress-inducing compound thapsigargin, 
      were highly susceptible to SMG1 inhibition. CC-115 caused the induction of UPR 
      transcripts and cell death by mitochondrial apoptosis, requiring the presence of 
      BAX/BAK and caspase activity. Superior antitumor activity of CC-115 over TORK 
      inhibitors in primary human MM cells and three xenograft mouse models appeared to 
      be via inhibition of SMG1. Our data support further development of SMG1 
      inhibitors as possible therapeutics in MM.
CI  - (c) 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on 
      behalf of Federation of European Biochemical Societies.
FAU - Leeksma, Alexander C
AU  - Leeksma AC
AUID- ORCID: 0000-0002-5576-7415
AD  - Department of Hematology, Amsterdam University Medical Centers, University of 
      Amsterdam, The Netherlands.
AD  - Department of Experimental Immunology, Amsterdam University Medical Centers, 
      University of Amsterdam, The Netherlands.
AD  - Lymphoma and myeloma center Amsterdam (LYMMCARE), Cancer Center Amsterdam (CCA) 
      and Amsterdam Infection and Immunity Institute (AIII), The Netherlands.
FAU - Derks, Ingrid A M
AU  - Derks IAM
AD  - Department of Experimental Immunology, Amsterdam University Medical Centers, 
      University of Amsterdam, The Netherlands.
AD  - Lymphoma and myeloma center Amsterdam (LYMMCARE), Cancer Center Amsterdam (CCA) 
      and Amsterdam Infection and Immunity Institute (AIII), The Netherlands.
FAU - Garrick, Brett
AU  - Garrick B
AD  - Translational Research, Bristol Myers Squibb, San Francisco, CA, USA.
FAU - Jongejan, Aldo
AU  - Jongejan A
AD  - Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam 
      University Medical Centers, University of Amsterdam, The Netherlands.
FAU - Colombo, Martino
AU  - Colombo M
AD  - Bristol Myers Squibb's Center for Innovation and Translational Research Europe 
      (CITRE), Seville, Spain.
FAU - Bloedjes, Timon
AU  - Bloedjes T
AD  - Department of Pathology, Amsterdam University Medical Centers, Lymphoma and 
      Myeloma Center Amsterdam (LYMMCARE), University of Amsterdam, The Netherlands.
FAU - Trowe, Torsten
AU  - Trowe T
AD  - Translational Research, Bristol Myers Squibb, San Francisco, CA, USA.
FAU - Leisten, Jim C
AU  - Leisten JC
AD  - Discovery, Bristol Myers Squibb, San Diego, CA, USA.
FAU - Howarth, Michelle
AU  - Howarth M
AD  - Translational Research, Bristol Myers Squibb, San Francisco, CA, USA.
FAU - Malek, Mehnaz
AU  - Malek M
AD  - Translational Research, Bristol Myers Squibb, San Francisco, CA, USA.
FAU - Mortensen, Deborah S
AU  - Mortensen DS
AUID- ORCID: 0000-0002-9144-0962
AD  - Discovery, Bristol Myers Squibb, San Diego, CA, USA.
FAU - Blease, Kate
AU  - Blease K
AD  - Discovery, Bristol Myers Squibb, San Diego, CA, USA.
FAU - Groza, Mathew C
AU  - Groza MC
AD  - Discovery, Bristol Myers Squibb, San Diego, CA, USA.
FAU - Narla, Rama Krishna
AU  - Narla RK
AD  - Discovery, Bristol Myers Squibb, San Diego, CA, USA.
FAU - Loos, Remco
AU  - Loos R
AD  - Bristol Myers Squibb's Center for Innovation and Translational Research Europe 
      (CITRE), Seville, Spain.
FAU - Kersten, Marie-Jose
AU  - Kersten MJ
AD  - Department of Hematology, Amsterdam University Medical Centers, University of 
      Amsterdam, The Netherlands.
FAU - Moerland, Perry D
AU  - Moerland PD
AD  - Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam 
      University Medical Centers, University of Amsterdam, The Netherlands.
FAU - Guikema, Jeroen E J
AU  - Guikema JEJ
AUID- ORCID: 0000-0001-6894-3441
AD  - Department of Pathology, Amsterdam University Medical Centers, Lymphoma and 
      Myeloma Center Amsterdam (LYMMCARE), University of Amsterdam, The Netherlands.
FAU - Kater, Arnon P
AU  - Kater AP
AD  - Department of Hematology, Amsterdam University Medical Centers, University of 
      Amsterdam, The Netherlands.
AD  - Lymphoma and myeloma center Amsterdam (LYMMCARE), Cancer Center Amsterdam (CCA) 
      and Amsterdam Infection and Immunity Institute (AIII), The Netherlands.
FAU - Eldering, Eric
AU  - Eldering E
AD  - Department of Experimental Immunology, Amsterdam University Medical Centers, 
      University of Amsterdam, The Netherlands.
AD  - Lymphoma and myeloma center Amsterdam (LYMMCARE), Cancer Center Amsterdam (CCA) 
      and Amsterdam Infection and Immunity Institute (AIII), The Netherlands.
FAU - Filvaroff, Ellen H
AU  - Filvaroff EH
AD  - Translational Research, Bristol Myers Squibb, San Francisco, CA, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221216
PL  - United States
TA  - Mol Oncol
JT  - Molecular oncology
JID - 101308230
RN  - 9007-49-2 (DNA)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (SMG1 protein, human)
RN  - EC 2.7.11.1 (Smg1 protein, mouse)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Mice
MH  - Cell Line
MH  - DNA/metabolism
MH  - Mammals/genetics/metabolism
MH  - *Multiple Myeloma/drug therapy/genetics
MH  - *Nonsense Mediated mRNA Decay/genetics
MH  - Protein Kinases/metabolism
MH  - Protein Serine-Threonine Kinases/genetics/metabolism
PMC - PMC9892823
OTO - NOTNLM
OT  - MM
OT  - NMD
OT  - SMG1
OT  - UPR
OT  - cancer
OT  - therapy
COIS- This work was sponsored via a research agreement between Amsterdam University 
      Medical Centers and Bristol Myers Squibb. BG, MH, MM, DM, KB, MC, JCL, MCG, RKN, 
      RL, TT, and EHF were/are employees of Bristol Myers Squibb. The remaining authors 
      declare no conflict of interest.
EDAT- 2022/11/19 06:00
MHDA- 2023/02/04 06:00
PMCR- 2022/12/16
CRDT- 2022/11/18 20:23
PHST- 2022/10/16 00:00 [revised]
PHST- 2022/08/01 00:00 [received]
PHST- 2022/11/17 00:00 [accepted]
PHST- 2022/11/19 06:00 [pubmed]
PHST- 2023/02/04 06:00 [medline]
PHST- 2022/11/18 20:23 [entrez]
PHST- 2022/12/16 00:00 [pmc-release]
AID - MOL213343 [pii]
AID - 10.1002/1878-0261.13343 [doi]
PST - ppublish
SO  - Mol Oncol. 2023 Feb;17(2):284-297. doi: 10.1002/1878-0261.13343. Epub 2022 Dec 
      16.