SMG1, a nonsense-mediated mRNA decay (NMD) regulator, as a candidate therapeutic target in multiple myeloma.

Autor: Leeksma AC; Department of Hematology, Amsterdam University Medical Centers, University of Amsterdam, The Netherlands.; Department of Experimental Immunology, Amsterdam University Medical Centers, University of Amsterdam, The Netherlands.; Lymphoma and myeloma center Amsterdam (LYMMCARE), Cancer Center Amsterdam (CCA) and Amsterdam Infection and Immunity Institute (AIII), The Netherlands., Derks IAM; Department of Experimental Immunology, Amsterdam University Medical Centers, University of Amsterdam, The Netherlands.; Lymphoma and myeloma center Amsterdam (LYMMCARE), Cancer Center Amsterdam (CCA) and Amsterdam Infection and Immunity Institute (AIII), The Netherlands., Garrick B; Translational Research, Bristol Myers Squibb, San Francisco, CA, USA., Jongejan A; Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam University Medical Centers, University of Amsterdam, The Netherlands., Colombo M; Bristol Myers Squibb's Center for Innovation and Translational Research Europe (CITRE), Seville, Spain., Bloedjes T; Department of Pathology, Amsterdam University Medical Centers, Lymphoma and Myeloma Center Amsterdam (LYMMCARE), University of Amsterdam, The Netherlands., Trowe T; Translational Research, Bristol Myers Squibb, San Francisco, CA, USA., Leisten JC; Discovery, Bristol Myers Squibb, San Diego, CA, USA., Howarth M; Translational Research, Bristol Myers Squibb, San Francisco, CA, USA., Malek M; Translational Research, Bristol Myers Squibb, San Francisco, CA, USA., Mortensen DS; Discovery, Bristol Myers Squibb, San Diego, CA, USA., Blease K; Discovery, Bristol Myers Squibb, San Diego, CA, USA., Groza MC; Discovery, Bristol Myers Squibb, San Diego, CA, USA., Narla RK; Discovery, Bristol Myers Squibb, San Diego, CA, USA., Loos R; Bristol Myers Squibb's Center for Innovation and Translational Research Europe (CITRE), Seville, Spain., Kersten MJ; Department of Hematology, Amsterdam University Medical Centers, University of Amsterdam, The Netherlands., Moerland PD; Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam University Medical Centers, University of Amsterdam, The Netherlands., Guikema JEJ; Department of Pathology, Amsterdam University Medical Centers, Lymphoma and Myeloma Center Amsterdam (LYMMCARE), University of Amsterdam, The Netherlands., Kater AP; Department of Hematology, Amsterdam University Medical Centers, University of Amsterdam, The Netherlands.; Lymphoma and myeloma center Amsterdam (LYMMCARE), Cancer Center Amsterdam (CCA) and Amsterdam Infection and Immunity Institute (AIII), The Netherlands., Eldering E; Department of Experimental Immunology, Amsterdam University Medical Centers, University of Amsterdam, The Netherlands.; Lymphoma and myeloma center Amsterdam (LYMMCARE), Cancer Center Amsterdam (CCA) and Amsterdam Infection and Immunity Institute (AIII), The Netherlands., Filvaroff EH; Translational Research, Bristol Myers Squibb, San Francisco, CA, USA.
Jazyk: angličtina
Zdroj: Molecular oncology [Mol Oncol] 2023 Feb; Vol. 17 (2), pp. 284-297. Date of Electronic Publication: 2022 Dec 16.
DOI: 10.1002/1878-0261.13343
Abstrakt: 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.
(© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
Databáze: MEDLINE
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