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

Abstract

Early data suggested that CC-115, a clinical molecule, already known to inhibit the mammalian target of rapamycin kinase (TORK) and DNAdependent 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 SMG1mediated 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.

In Vitro Cross-Linking MS Reveals SMG1–UPF2–SMG7 Assembly as Molecular Partners within the NMD Surveillance

“…Along with having a crucial role in identifying the SMG1–UPF2–SMG7 complex within the NMD process, the SMG1 genes have been shown distinguishable in tasks in the alternative splicing of the tumour-suppressor p53 genes [ 25 ]. Due to the different activities of SMG1 in multiple myeloma (MM) cell lines [ 26 ], it has become a promising therapeutic target for the development of novel drug molecules. The activation of the SMG1-UPF within the NMD pathway has shown a downregulation of negative regulator MDM2 (Murine Double Minute Clone 2) by Glaucocalyxin A in Gastric cancer (GC) cells [ 27 ].…”

The Art of Finding the Right Drug Target: Emerging Methods and Strategies

“…One study found potential targets by targeting the key NMD factor UPF1 to bind the fragile X syndrome protein FMRP (Kurosaki et al, 2021). The NMD regulator SMG1 has been shown to be a candidate therapeutic target for multiple myeloma (Leeksma et al, 2023). Moreover, relevant studies have shown that the NMD factor UPF2 is a key target for the treatment of early embryonic lethality (Chousal et al, 2022).…”

Identification of novel tumor antigens and immune subtypes in breast cancer patients for mRNA vaccine development

“…The latter can detect and destroy aberrant transcripts with premature termination codons (PTCs), preventing potentially harmful proteins from being translated [10]. During the process, a number of frameshift mutations may avert from NMD, and probably induce immune reactions [11]. Many previous studies also have indicated that abnormal transcripts which evade from NMD may encode neoantigens potentially triggering immune responses in cancer patients [12][13][14].…”