<i>SRP19</i> and the protein secretion machinery is a targetable vulnerability in cancers with <i>APC</i> loss.

Abstract

Loss of the tumor suppressor gene (TSG) Adenomatous Polyposis Coli (<i>APC</i>) 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 <i>SRP19</i> and the protein secretion machinery as a unique vulnerability in cancers with heterozygous <i>APC</i> loss. <i>SRP19</i> is located 15 kb from <i>APC</i> and is almost always codeleted in these tumors. Heterozygous <i>APC/SRP19</i> loss leads to lower levels of <i>SRP19</i> mRNA and protein. Consequently, cells with <i>APC/SRP19</i> loss are vulnerable to partial suppression of <i>SRP19</i>. Moreover, we show that <i>SRP19</i> is rate limiting for the formation of the Signal Recognition Particle, a complex that mediates ER-protein translocation, and thus, heterozygous <i>SRP19</i> 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 <i>APC</i> deletion and provides a framework for identifying and translating vulnerabilities associated with loss of a TSG.