SRP19 and the protein secretion machinery is a targetable vulnerability in cancers with APC loss

Abstract

Adenomatous Polyposis Coli (APC) is a tumour suppressor that is frequently lost in colorectal and other cancers. A common mechanism for APC loss includes heterozygous APC deletion. Here, we show that SRP19, is located near APC and is often co-deleted in these tumours. Heterozygous APC/SRP19 loss leads to lower levels of SRP19 mRNA and protein. Consequently, cells with APC/SRP19 loss are vulnerable to partial suppression of SRP19. We show that SRP19 loss is a unique vulnerability since SRP19 is 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, partial SRP19 knock-down or low dose Arsenic Trioxide treatment induces ER stress and inhibits proliferation in APC/SRP19 loss cancers. Our work identifies a new strategy to treat cancers with APC/SRP19 heterozygous deletions and provides a framework for identifying vulnerabilities associated with loss of a tumour suppressor.