Identification of nonsense-mediated decay inhibitors that alter the tumor immune landscape

Author:

Cook Ashley L12ORCID,Sur Surojit134,Dobbyn Laura3,Watson Evangeline1,Cohen Joshua D134,Ptak Blair3,Lee Bum Seok3,Paul Suman134,Hsiue Emily1,Popoli Maria1,Vogelstein Bert12345,Papadopoulos Nickolas134,Bettegowda Chetan12346,Gabrielson Kathy347,Zhou Shibin134,Kinzler Kenneth W12348,Wyhs Nicolas134ORCID

Affiliation:

1. Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine

2. Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine

3. Department of Oncology, Johns Hopkins Medical Institutions

4. Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine

5. Howard Hughes Medical Institute, Johns Hopkins University School of Medicine

6. Department of Neurosurgery, Johns Hopkins University School of Medicine

7. Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine

8. Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine

Abstract

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.

Publisher

eLife Sciences Publications, Ltd

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