美国博德研究所Francisca Vazquez等研究人员合作发现，SKI复合体丧失使9p21.3缺失或MSI-H癌症依赖PELO。相关论文于2025年2月5日在线发表于国际学术期刊《自然》。

研究人员分析了来自癌症依赖性图谱的大规模CRISPR敲除筛选数据，发现了一个新的合成致死靶点PELO，其适用于两种独立的癌症分子亚型：染色体区域9p21.3的双等位基因缺失或微卫星不稳定性高（MSI-H）。

在9p21.3缺失的癌症中，PELO依赖性来源于9p21.3基因FOCAD的双等位基因缺失，FOCAD是超杀复合体（SKIc）的稳定因子。在MSI-H癌症中，PELO的需求源自于与MSI-H相关的TTC37突变（也称为SKIC3），TTC37是SKIc的关键组分。

研究人员展示了这两种癌症亚型趋向于通过不稳定化SKIc来发挥作用，SKIc提取停滞的核糖体上的mRNA。在缺乏SKIc的细胞中，PELO缺失会诱导未折叠蛋白反应，这是对未折叠或错误折叠的初生多肽积累的应激反应。

总的来说，研究结果表明，PELO是一个有前景的治疗靶点，适用于大量患有MSI-H特征、具有有害TTC37突变或涉及FOCAD的双等位基因9p21.3缺失的癌症患者群体。

据了解，癌症基因组改变常常导致一些脆弱性，可以用来选择性地靶向癌细胞。各种针对这种合成致死靶点的抑制剂，已经获得FDA批准或正在临床试验中，突显了这一方法的潜力。

附：英文原文

Title: SKI complex loss renders 9p21.3-deleted or MSI-H cancers dependent on PELO

Author: Borck, Patricia C., Boyle, Isabella, Jankovic, Kristina, Bick, Nolan, Foster, Kyla, Lau, Anthony C., Parker-Burns, Lucy I., Lubicki, Daniel A., Li, Tianxia, Borah, Ashir A., Lofaso, Nicholas J., Das Sharma, Sohani, Chan, Tessla, Kishen, Riya V., Adeagbo, Anisah, Raghavan, Srivatsan, Aquilanti, Elisa, Prensner, John R., Krill-Burger, J. Michael, Golub, Todd R., Campbell, Catarina D., Dempster, Joshua M., Chan, Edmond M., Vazquez, Francisca

Issue&Volume: 2025-02-05

Abstract: Cancer genome alterations often lead to vulnerabilities that can be used to selectively target cancer cells. Various inhibitors of such synthetic lethal targets have been approved by the FDA or are in clinical trials, highlighting the potential of this approach1,2,3. Here we analysed large-scale CRISPR knockout screening data from the Cancer Dependency Map and identified a new synthetic lethal target, PELO, for two independent molecular subtypes of cancer: biallelic deletion of chromosomal region 9p21.3 or microsatellite instability-high (MSI-H). In 9p21.3-deleted cancers, PELO dependency emerges from biallelic deletion of the 9p21.3 gene FOCAD, a stabilizer of the superkiller complex (SKIc). In MSI-H cancers, PELO is required owing to MSI-H-associated mutations in TTC37 (also known as SKIC3), a critical component of the SKIc. We show that both cancer subtypes converge to destabilize the SKIc, which extracts mRNA from stalled ribosomes. In SKIc-deficient cells, PELO depletion induces the unfolded protein response, a stress response to accumulation of misfolded or unfolded nascent polypeptides. Together, our findings indicate PELO as a promising therapeutic target for a large patient population with cancers characterized as MSI-H with deleterious TTC37 mutations or with biallelic 9p21.3 deletions involving FOCAD.

DOI: 10.1038/s41586-024-08509-3

Source: https://www.nature.com/articles/s41586-024-08509-3