SRP19and the protein secretion machinery is a targetable vulnerability in cancers withAPCloss

Abstract

AbstractAdenomatous Polyposis Coli (APC) is a tumour suppressor that is frequently lost in colorectal and other cancers. A common mechanism forAPCloss includes heterozygousAPCdeletion. Here, we show thatSRP19, is located nearAPCand is often co-deleted in these tumours. HeterozygousAPC/SRP19loss leads to lower levels ofSRP19mRNA and protein. Consequently, cells withAPC/SRP19loss are vulnerable to partial suppression ofSRP19. We show thatSRP19loss is a unique vulnerability sinceSRP19is rate limiting for the formation of the Signal Recognition Particle (SRP), a complex that mediates translocation of proteins to the ER. Consistent with these observations, partialSRP19knock-down or low dose Arsenic Trioxide treatment induces ER stress and inhibits proliferation inAPC/SRP19loss cancers. Our work identifies a new strategy to treat cancers withAPC/SRP19heterozygous deletions and provides a framework for identifying vulnerabilities associated with loss of a tumour suppressor.