Nonsense-mediated mRNA decay, the achilles heel of recurrent glioblastoma?
Vassella group Prof. Dr. Erik Vassella
We conducted CRISPR/CAS interference library screens and identified SMG1, implicated in an evolutionarily conserved RNA quality control pathway - the nonsense-mediated mRNA decay (NMD) pathway. NMD leads to the degradation of transcripts containing premature stop codons, often occurring after temozolomide treatment.
NMD may influence the mechanisms employed by tumour cells to repair DNA damage caused by temozolomide treatment. Hence, we hypothesise that the enhanced temozolomide response is due to reduced DNA repair capacity in SMG1-attenuated glioblastoma cells.
The aim of this work is to further investigate the mechanisms leading to an enhanced temozolomide response in glioblastoma cells with attenuated SMG1. Since NMD efficiently suppresses truncated proteins, which are highly immunogenic, we hypothesise that SMG1 inhibition in temozolomide-resistant, recurrent glioblastoma may elicit tumour inflammation. Hence, we expect that NMD improves the treatment response to immune checkpoint inhibitors. This work is currently supported by the Swiss Cancer League.