SMG1, a nonsense-mediated mRNA decay (NMD) regulator, as a candidate therapeutic target in multiple myeloma.
Alexander C LeeksmaIngrid A M DerksBrett GarrickAldo JongejanMartino ColomboTimon BloedjesTorsten TroweJim C LeistenMichelle HowarthMehnaz MalekDeborah S MortensenKate BleaseMathew C GrozaRama Krishna NarlaRemco LoosMarie-José KerstenPerry D MoerlandJeroen E J GuikemaArnon P KaterEric ElderingEllen H FilvaroffPublished in: Molecular oncology (2022)
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 induction of UPR transcripts and cell death by mitochondrial apoptosis, requiring presence of BAX/BAK and caspase activity. Superior anti-tumor 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.
Keyphrases
- induced apoptosis
- endoplasmic reticulum stress
- cell death
- protein kinase
- cell cycle arrest
- multiple myeloma
- oxidative stress
- circulating tumor
- cell free
- single molecule
- signaling pathway
- nucleic acid
- electronic health record
- mouse model
- transcription factor
- big data
- endothelial cells
- tyrosine kinase
- small molecule
- squamous cell carcinoma
- data analysis
- combination therapy
- induced pluripotent stem cells
- replacement therapy
- young adults
- smoking cessation
- pluripotent stem cells
- artificial intelligence