RNA-seq data for LS180 and NCI-H358 Cancer cell lines

Despite exciting developments in cancer immunotherapy, its broad
application is limited by the paucity of targetable antigens on the tumor
cell surface. As an intrinsic cellular pathway, nonsense-mediated decay
(NMD) conceals neoantigens through the destruction of the RNA products
from genes harboring truncating mutations. We developed and conducted a
high throughput screen, based on the ratiometric analysis of transcripts,
to identify critical mediators of NMD. This screen revealed disruption of
kinase SMG1’s phosphorylation of UPF1 as a potent disruptor of NMD. This
led us to design a novel SMG1 inhibitor, KVS0001, that elevates the
expression of transcripts and proteins resulting from truncating mutations
in vivo and in vitro. Most importantly, KVS0001 concomitantly increased
the presentation of immune-targetable HLA class I-associated peptides from
NMD-downregulated proteins on the surface of cancer cells. KVS0001
provides new opportunities for studying NMD and the diseases in which NMD
plays a role, including cancer and inherited diseases.