[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-338006-105":59,"doc-detail-338006-en":131},{"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":124,"head_meta":126,"extra_data":128,"updated_unix":130},105,"en","brca1-secondary-splice-site-mutations-drive-exon-skipping-and-parp-inhibitor-resistance","BRCA1 secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance","","PARP inhibitor therapy improves outcomes for homologous recombination DNA repair (HRR) deficient ovarian cancers, yet resistance frequently develops. Secondary mutations that restore the HR gene reading frame can drive this resistance, including BRCA1 splice isoforms that splice out mutation-containing exons, producing truncated hypomorphic proteins. The clinical impacts and drivers of BRCA1 exon skipping remain insufficiently understood, prompting direct analysis of patient-derived models and clinical cohorts.",{"@graph":69,"@context":123},[70,84,106],{"@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/brca1-secondary-splice-site-mutations-drive-exon-skipping-and-parp-inhibitor-resistance/338006/",{"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/brca1-secondary-splice-site-mutations-drive-exon-skipping-and-parp-inhibitor-resistance/338006.png","ImageObject",300,407,{"name":92,"@type":93},"Oliver","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",13,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"How can BRCA1 exon skipping contribute to PARP inhibitor resistance?","Question",{"text":113,"@type":114},"BRCA1 splice isoforms can splice out mutation-containing exons, generating truncated but partially functional proteins. These hypomorphic proteins can support resistance despite the initial HRR deficiency.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"What evidence supports exon skipping as a resistance mechanism?",{"text":118,"@type":114},"Nine ovarian and breast cancer patient-derived xenografts with BRCA1 exon 11 frameshift mutations were analyzed. PARPi-resistant tumors showed elevated exon 11 skipping, and secondary BRCA1 splice-site mutations were validated using qRT-PCR, RNA sequencing, immunoblotting, and minigene modeling.",{"name":120,"@type":111,"acceptedAnswer":121},"Are the identified secondary splice-site mutations observed in clinical settings?",{"text":122,"@type":114},"Yes. Secondary BRCA1 splice-site mutations were enriched in post-PARPi ovarian cancer patient cohorts from the ARIEL2 and ARIEL4 clinical trials, supporting clinical relevance.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},338006,1790144470,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":52,"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","Nesic etal. Molecular Cancer (2024) 23:158 [https://doi.org/10.1186/s12943-024-02048-1](https://doi.org/10.1186/s12943-024-02048-1)  \nMolecular Cancer  \n CORRESPONDENCE Open Access  \nBRCA1 secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance  \nKsenija Nesic1,2†, John J. Krais3,4†, Yifan Wang3, Cassandra J. Vandenberg 1,2, Pooja Patel3, Kathy Q. Cai3, Tanya Kwan5, Elizabeth Lieschke1,2, Gwo-Yaw Ho6, Holly E. Barker 1,2, Justin Bedo 1,2, Silvia Casadei7, Andrew Farrell1,2, Marc Radke7, Kristy Shield-Artin1,2, Jocelyn S. Penington 1,2, Franziska Geissler1,2, Elizabeth Kyran1,2, Robert Betsch3, Lijun Xu8,9, Fan Zhang10, Alexander Dobrovic10, Inger Olesen11, Rebecca Kristeleit 12,13, Amit Oza14, Iain McNeish 15, Gayanie Ratnayake 16, Nadia Traficante17,18, Australian Ovarian Cancer Study, Anna DeFazio19,20,21, David D. L. Bowtell 17,18, Thomas C. Harding5, Kevin Lin5, Elizabeth M. Swisher7, Olga Kondrashova 1,8,9, Clare L. Scott 1,2,16,17,18,22*†, Neil Johnson3*† and Matthew J. Wakefield 1,2,22*†  \nAbstract  \nPARP inhibitor (PARPi) therapy has transformed outcomes for patients with homologous recombination DNA repair (HRR) deficient ovarian cancers, for example those with BRCA1 or BRCA2 gene defects. Unfortunately, PARPi resistance is common. Multiple resistance mechanisms have been described, including secondary mutations that restore the HR gene reading frame. BRCA1 splice isoforms △11 and △11q can contribute to PARPi resistance by splicing out the mutation-containing exon, producing truncated, partially functional proteins. However, the clinical impactsand underlying drivers of BRCA1 exon skipping are not fully understood.  \nWe analyzed nine ovarian and breast cancer patient derived xenografts (PDX) with BRCA1 exon 11 frameshift mutations for exon skipping and therapy response, including a matched PDX pair derived from a patient pre-and postchemotherapy/PARPi. BRCA1 exon 11 skipping was elevated in PARPi resistant PDX tumors. Two independent PDX models acquired secondary BRCA1 splice site mutations (SSMs) that drive exon skipping, confirmed using qRT-PCR, RNA sequencing, immunoblotting and minigene modelling. CRISPR/Cas9-mediated disruption of splicing functionally validated exon skipping as a mechanism of PARPi resistance. SSMs were also enriched in post-PARPi ovarian cancer patient cohorts from the ARIEL2 and ARIEL4 clinical trials.  \nFew PARPi resistance mechanisms have been confirmed in the clinical setting. While secondary/reversion mutations typically restore a gene’s reading frame, we have identified secondary mutations in patient cohorts that hijack splice sites to enhance mutation-containing exon skipping, resulting in the overexpression of BRCA1 hypomorphs, which  \n\n| †Ksenija Nesic and John J. Krais joint first authors. |\n| --- |\n| †Clare L. Scott, Neil Johnson and Matthew J. Wakefield joint senior authors. |\n\n*Correspondence: Clare L. Scott [scottc@wehi.edu.au](scottc@wehi.edu.au)[ ](scottc@wehi.edu.au)Neil Johnson [Neil.Johnson@fccc.edu](Neil.Johnson@fccc.edu)[ ](Neil.Johnson@fccc.edu)Matthew J. Wakefield  \n[matthew.wakefield@unimelb.edu.au](matthew.wakefield@unimelb.edu.au)  \nFull list of author information is available at the end of the article  \n© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in ","cbCaihEnj1CXuv5u","https://ap.wps.com/l/cbCaihEnj1CXuv5u","pdf",2538313,"English","# Abstract\n## BRCA1 splice mutations and PARP inhibitor resistance\n## Evidence from PDX models and validation methods\n## Clinical enrichment in ARIEL trials and implications\n# Introduction\n## HRR deficiency and PARPi sensitivity","[{\"question\":\"How can BRCA1 exon skipping contribute to PARP inhibitor resistance?\",\"answer\":\"BRCA1 splice isoforms can splice out mutation-containing exons, generating truncated but partially functional proteins. These hypomorphic proteins can support resistance despite the initial HRR deficiency.\"},{\"question\":\"What evidence supports exon skipping as a resistance mechanism?\",\"answer\":\"Nine ovarian and breast cancer patient-derived xenografts with BRCA1 exon 11 frameshift mutations were analyzed. PARPi-resistant tumors showed elevated exon 11 skipping, and secondary BRCA1 splice-site mutations were validated using qRT-PCR, RNA sequencing, immunoblotting, and minigene modeling.\"},{\"question\":\"Are the identified secondary splice-site mutations observed in clinical settings?\",\"answer\":\"Yes. Secondary BRCA1 splice-site mutations were enriched in post-PARPi ovarian cancer patient cohorts from the ARIEL2 and ARIEL4 clinical trials, supporting clinical relevance.\"}]","BRCA1 secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance | PDF",1790021544,25]