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

Loss of the tumor suppressor gene (TSG) Adenomatous Polyposis Coli () is a hallmark event in colorectal cancers. Since it is not possible to directly target a TSG, no treatment options are available for these patients. Here, we identify and the protein secretion machinery as a unique vulnerability in cancers with heterozygous loss. is located 15 kb from and is almost always codeleted in these tumors. Heterozygous loss leads to lower levels of mRNA and protein. Consequently, cells with loss are vulnerable to partial suppression of . Moreover, we show that is rate limiting for the formation of the Signal Recognition Particle, a complex that mediates ER-protein translocation, and thus, heterozygous loss leads to less protein secretion and higher levels of ER-stress. As a result, low-dose arsenic trioxide induces ER-stress and inhibits proliferation in cultured cell lines and animal models. Our work identifies a strategy to treat cancers with deletion and provides a framework for identifying and translating vulnerabilities associated with loss of a TSG.