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

Alexander C Leeksma, Ingrid A M Derks, Brett Garrick, Aldo Jongejan, Martino Colombo, Timon Bloedjes, Torsten Trowe, Jim C Leisten, Michelle Howarth, Mehnaz Malek, Deborah S Mortensen, Kate Blease, Mathew C Groza, Rama Krishna Narla, Remco Loos, Marie-José Kersten, Perry D Moerland, Jeroen E J Guikema, Arnon P Kater, Eric ElderingEllen H Filvaroff

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
JournalMolecular Oncology
Early online date18 Nov 2022
DOIs
Publication statusE-pub ahead of print - 18 Nov 2022

Keywords

  • MM
  • NMD
  • SMG1
  • UPR
  • cancer
  • therapy

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