[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-364611-105":59,"doc-detail-364611-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","ski-complex-loss-renders-9p213-deleted-or-msi-h-cancers-dependent-on-pelo","SKI complex loss renders 9p21.3-deleted or MSI-H cancers dependent on PELO","","Cancer genome alterations can create selective vulnerabilities that enable targeted elimination of tumour cells. Large-scale CRISPR knockout screening using the Cancer Dependency Map identified PELO as a new synthetic lethal target in two molecular cancer subtypes: 9p21.3 biallelic deletion and microsatellite instability-high (MSI-H). In 9p21.3-deleted cancers, PELO dependence links to biallelic deletion of FOCAD. In MSI-H cancers, it arises from MSI-H mutations in TTC37 (SKIC3). Both converge on destabilizing the SKIc and triggering an unfolded protein response after PELO depletion.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/ski-complex-loss-renders-9p213-deleted-or-msi-h-cancers-dependent-on-pelo/364611/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/ski-complex-loss-renders-9p213-deleted-or-msi-h-cancers-dependent-on-pelo/364611.png","ImageObject",300,407,{"name":92,"@type":93},"Oliver","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-24","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":34},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is PELO in the context of this study?","Question",{"text":112,"@type":113},"PELO is identified as a new synthetic lethal dependency selectively required in specific cancer subtypes, including 9p21.3-deleted and MSI-H cancers.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does PELO dependency arise in 9p21.3-deleted cancers?",{"text":117,"@type":113},"Dependency emerges from biallelic deletion of the 9p21.3 gene FOCAD, which affects stabilization of the superkiller complex (SKIc).",{"name":119,"@type":110,"acceptedAnswer":120},"Why are MSI-H cancers dependent on PELO?",{"text":121,"@type":113},"MSI-H cancers require PELO due to MSI-H-associated mutations in TTC37 (SKIC3), a critical component of the SKIc.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},364611,1790663946,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":34,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},8796095461610,"https://ap-avatar.wpscdn.com/davatar_276721f389ce27ea32af1340a28f341c","Article  \nSKI complex loss renders 9p21.3-deleted or MSI-H cancers dependent on PELO  \n\n| [https://doi.org/10.1038/s41586-024-08509-3](https://doi.org/10.1038/s41586-024-08509-3)\u003Cbr>Received: 27 April 2024 Accepted: 10 December 2024 Published online: 5 February 2025 Open access\u003Cbr> Check for updates | Patricia C. Borck1, Isabella Boyle1, Kristina Jankovic2, Nolan Bick1, Kyla Foster1, Anthony C. Lau1, Lucy I. Parker-Burns2, Daniel A. Lubicki1, Tianxia Li2, Ashir A. Borah1, Nicholas J. Lofaso2, Sohani Das Sharma2, Tessla Chan2, Riya V. Kishen2, AnisahAdeagbo1, Srivatsan Raghavan1,3, Elisa Aquilanti1,4, John R. Prensner1,5, J. Michael Krill-Burger1, Todd R. Golub1,6, Catarina D. Campbell1, Joshua M. Dempster1, Edmond M. Chan1,2,7,8,9✉ & FranciscaVazquez1,9✉\u003Cbr>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 approach1–3. Here we analysed large-scale CRISPR knockout screening data from the Cancer Dependency Map and identified anew 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-Hcancers, PELOis 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 asa promising therapeutic target fora large patient population with cancers characterized as MSI-H with deleterious TTC37 mutations or with biallelic 9p21.3 deletions involving FOCAD. |  |\n| --- | --- | --- |\n| Homozygous deletion of chromosomal region 9p21.3 is among the |  | codeleted genes may have critical roles in cell maintenance, and their |\n| most frequently observed somatic copy number alterations inhuman |  | loss can lead to newly acquired dependencies on related or paralogous |\n| cancers, occurring in approximately 13–15% of all cancers4,5 (Fig. 1a). |  | genes. For instance, large-scale RNA interference data from the Cancer |\n| Many 9p21.3-loss cancers are associated with poor clinical outcomes, |  | Dependency Map (DepMap) and Project Drive led to the discovery |\n| including subsets of glioblastoma, urothelial carcinoma of the bladder, |  | of PRMT5 as a promising target in 9p21.3−/− cancers through its syn- |\n| pancreatic ductaladenocarcinoma, oesophageal adenocarcinoma and |  | thetic lethal interactions with MTAP deletion19,20. Although clinical |\n| non-small-cell lung cancer6–11. Loss of tumour suppressors CDKN2A |  | trials of PRMT5 inhibitors and related MAT2A inhibitors for patients |\n| or CDKN2AB is thought to beakey driver of 9p21.3 deletions (9p21.3−/−) |  | forMTAP-deleted cancers are underway, the frequency, poor outcomes |\n| in cancers. However, recent studies suggest that deletions of neighbour- |  | and immune checkpoint inhibitor resistance associated with 9p21.3−/− |\n| ing genes are also important foroncogenesis, which might explain why |  | cancers highlight an urgent need for further therapeutic strategies for |\n| this chromosomal region is deleted rather than isolated inactivation of |  | this broad class of cancers21,22. |\n| CDKN2AorCDKN2BMTAP, which lies adjacent toCDKN2A, is a putative |  | Here, we used large-scale CRISPR knockout screening datasets from |\n| tumour suppressor gene that is frequently codeleted with CDKN2A |  | DepMap to identify further synthetic lethal targets associated with |\n| and CDKN2B12,13. St","cbCaiffh9W9fPhCs","https://ap.wps.com/l/cbCaiffh9W9fPhCs","pdf",26108078,21,"English","# Abstract and findings\n## Identification of PELO synthetic lethality\n## Mechanisms in 9p21.3-deleted cancers\n## Mechanisms in MSI-H cancers\n## Convergence on SKIc destabilization and unfolded protein response\n## Therapeutic implications for patient subgroups","[{\"question\":\"What is PELO in the context of this study?\",\"answer\":\"PELO is identified as a new synthetic lethal dependency selectively required in specific cancer subtypes, including 9p21.3-deleted and MSI-H cancers.\"},{\"question\":\"How does PELO dependency arise in 9p21.3-deleted cancers?\",\"answer\":\"Dependency emerges from biallelic deletion of the 9p21.3 gene FOCAD, which affects stabilization of the superkiller complex (SKIc).\"},{\"question\":\"Why are MSI-H cancers dependent on PELO?\",\"answer\":\"MSI-H cancers require PELO due to MSI-H-associated mutations in TTC37 (SKIC3), a critical component of the SKIc.\"}]","SKI complex loss renders 9p21.3-deleted or MSI-H cancers dependent on PELO | PDF",1790158543,53]