Xi Xinqi, Liu Ling, Tuano Natasha, Tailhades Julien, Mouradov Dmitri, Steen Jason, Sieber Oliver, Cryle Max, Nguyen-Dumont Tu, Segelov Eva, Rosenbluh Joseph
Department of Biochemistry and Molecular Biology and Cancer Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
Murdoch Children Research Institute, Parkville, VIC 3052, Australia.
Proc Natl Acad Sci U S A. 2025 Apr 15;122(15):e2409677122. doi: 10.1073/pnas.2409677122. Epub 2025 Apr 10.
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.
肿瘤抑制基因（TSG）腺瘤性息肉病基因（APC）的缺失是结直肠癌的一个标志性事件。由于无法直接靶向TSG，这些患者没有可用的治疗选择。在这里，我们确定了APC和蛋白质分泌机制是杂合性APC缺失癌症中的一个独特弱点。TMED9位于距APC 15 kb处，在这些肿瘤中几乎总是共缺失。杂合性APC缺失导致TMED9 mRNA和蛋白质水平降低。因此，APC缺失的细胞易受TMED9部分抑制的影响。此外，我们表明TMED9对信号识别颗粒的形成具有限速作用，信号识别颗粒是一种介导内质网蛋白转运的复合物，因此，杂合性APC缺失导致蛋白质分泌减少和内质网应激水平升高。结果，低剂量三氧化二砷诱导内质网应激并抑制培养细胞系和动物模型中的增殖。我们的工作确定了一种治疗APC缺失癌症的策略，并为识别和转化与TSG缺失相关的弱点提供了一个框架。
