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A synchronized two-stage proliferation design links lncRNA-mediated control of tumor growth with CDK4/6 inhibitor sensitivity. Integration of CRISPRa results with drug response profiles from 815 cancer cell lines identifies and validates TENM3-AS1, LINC01117, and ENSG00000226706 as lncRNAs that enhance CDK4/6 inhibitor sensitivity while promoting proliferation. In patients, these signatures associate with CDK4/6 inhibitor response, and TENM3-AS1 acts as a potential ERα-interacting lncRNA with ERα-dependent effects.",{"@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/crispr-activation-screens-identify-oncogenic-lncrnas-that-are-susceptible-to-cdk46-inhibitor-treatment/360616/",{"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/crispr-activation-screens-identify-oncogenic-lncrnas-that-are-susceptible-to-cdk46-inhibitor-treatment/360616.png","ImageObject",300,407,{"name":92,"@type":93},"Aran","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":39},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What screening approach is used to identify lncRNAs involved in CDK4/6 inhibitor response?","Question",{"text":112,"@type":113},"The study applies genome-wide and focused CRISPR activation (CRISPRa) screens with a synchronized two-stage proliferation design to connect lncRNA regulation with drug sensitivity.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Which lncRNAs are reported to increase breast cancer sensitivity to CDK4/6 inhibitors?",{"text":117,"@type":113},"The paper identifies and validates TENM3-AS1, LINC01117, and ENSG00000226706 as lncRNAs that increase CDK4/6 inhibitor sensitivity while promoting tumor proliferation.",{"name":119,"@type":110,"acceptedAnswer":120},"How is TENM3-AS1 mechanistically linked to CDK4/6 inhibitor sensitivity?",{"text":121,"@type":113},"The study shows lncRNATENM3-AS1 is a potential ERα-interacting lncRNA, and its regulation of CDK4/6 inhibitor sensitivity depends on ERα expression.","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},360616,1790548455,{"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":39,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":56,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":144},137455076865,"https://ap-avatar.wpscdn.com/davatar_29158cc5080c5b710cf443261637dec0","Article [https://doi.org/10.1038/s41467-026-70816-2](https://doi.org/10.1038/s41467-026-70816-2)  \nCRISPR activation screens identify oncogenic lncRNAs that are susceptible to CDK4/6 inhibitor treatment  \nReceived: 4 December 2024  \n\n| Accepted: 5 March 2026 |\n| --- |\n| |\n| Check for updates |\n\nYifei Wang 1,5, Yueshan Zhao1,5, Jiaxin Hu 1,5, Zehua Wang 1, Dhamotharan Pattarayan 1, Sihan Li1, Yu Zhang1, Xiaofei Wang 1, Yue Wang1, Wen Xie 1, Min Zhang2  & Da Yang 1,3,4   \nThe roles of long non-coding RNAs (lncRNAs) in tumorigenesis and therapeutic response remain largely unknown. Here we perform genome-wide and focused CRISPR activation screens to identify lncRNAs regulating palbociclib response in breast cancer cells. A synchronized two-stage proliferation screen not only characterizes tumor growth-regulating lncRNAs, but also reveals a strong negative correlation between lncRNA-mediated regulation of tumor proliferation and CDK4/6 inhibitor sensitivity. By integrating CRISPRa screen results with drug response data from 815 cancer cell lines, we identify and functionally validate that TENM3-AS1, LINC01117, and ENSG00000226706 can increase breast cancer sensitivity to CDK4/6i while promoting tumor proliferation. In breast cancer patients, all three lncRNA signatures are associated with CDK4/6 inhibitor response. Mechanistically, we have shown that lncRNATENM3-AS1 is a potential ERα-interacting lncRNA, and its regulation ofCDK4/6 inhibitor sensitivity is dependent on ERα expression. Our integrated strategy characterizes oncogenic lncRNAs as potential therapeutic biomarkers for CDK4/6 inhibitor treatment in cancer.  \nTremendous efforts have been made to better characterize novel cancer genes that can serve as targets and biomarkers of cancer treatment. Those large-scale, high-throughput genomics efforts, mainly focusing on protein-coding components of the genome, have led to many insightful discoveries1,2, but also new questions: few novel cancer genes have been identified to fully explain the molecular and clinical heterogeneity of tumor initiation, progression, and therapeutic response3. Recent large-scale studies, such asthe Encyclopedia of DNA Elements (ENCODE), have identified numerous long non-coding RNAs (lncRNAs)4,5. Further bioinformatics analyses of cancer transcriptome and epigenome have revealed that lncRNAs are among the most prevalent transcriptional changes in cancer6–9. Functional characterizations ofthe lncRNAs have suggested that some of them play important  \nroles in tumorigenesis5,10–14, metastasis15, and cancer treatment response9,16–20. For example, lncRNA HOTAIR has been found to augment ER signaling, leading to tamoxifen resistance in breast cancer patients21. Our previous research found that the oncogenic lncRNA EPIC1 contributes to Bromodomain and Extra-Terminal inhibitors (iBET) resistance by enhancing the transcriptional activity of the MYC protein9,22. Moreover, lncRNA EGFR-AS1 and MIR205HG are shown to regulate erlotinib sensitivity through in vitro studies and lung cancer patient cohorts16. Previous studies have also shown that lncRNA LEIGC inhibits the epithelial-to-mesenchymal transition and enhances the sensitivity to 5-fluorouracil in gastric cancer23.  \nDespite these advancements, the function of the vast majority of lncRNAs in cancer initiation, progression, and treatment response  \n1Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA. 2Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA. 3UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. 4Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA. 5These authors contributed equally: Yifei Wang, Yueshan Zhao, Jiaxin Hu.  \n[e-mail:](e-mail: miz45@pitt.edu)[ miz45@pitt.edu](e-mail: miz45@pitt.edu); [dyang@pitt.edu](dyang@pitt.edu)  \nremains elusive. Most of the discoveries on novel lncRNAs start ","cbCaisimhXx8mNNk","https://ap.wps.com/l/cbCaisimhXx8mNNk","pdf",6091767,"English","# CRISPRa screening strategy for lncRNA sensitivity\n## Link between lncRNA regulation and CDK4/6 inhibitor response\n## Identified lncRNA candidates and patient association\n## Mechanistic role of lncRNATENM3-AS1 via ERα\n# Background on lncRNAs and functional genomics\n## Limitations of computational discovery and loss-of-function screens\n## Rationale for CRISPRa gain-of-function approaches\n# CDK4/6 inhibitor context in breast cancer\n## Approved inhibitors and clinical use\n## Targeting cell-cycle progression in ER+ / HER2- disease","[{\"question\":\"What screening approach is used to identify lncRNAs involved in CDK4/6 inhibitor response?\",\"answer\":\"The study applies genome-wide and focused CRISPR activation (CRISPRa) screens with a synchronized two-stage proliferation design to connect lncRNA regulation with drug sensitivity.\"},{\"question\":\"Which lncRNAs are reported to increase breast cancer sensitivity to CDK4/6 inhibitors?\",\"answer\":\"The paper identifies and validates TENM3-AS1, LINC01117, and ENSG00000226706 as lncRNAs that increase CDK4/6 inhibitor sensitivity while promoting tumor proliferation.\"},{\"question\":\"How is TENM3-AS1 mechanistically linked to CDK4/6 inhibitor sensitivity?\",\"answer\":\"The study shows lncRNATENM3-AS1 is a potential ERα-interacting lncRNA, and its regulation of CDK4/6 inhibitor sensitivity depends on ERα expression.\"}]","CRISPR activation screens identify oncogenic lncRNAs that are susceptible to CDK4/6 inhibitor treatment | PDF",1790140725,48]