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DLK1, a delta-like non-canonical Notch ligand 1 (DLK1), is identified as a cell-surface protein with limited normal tissue expression and high expression in refractory adult metastatic cancers, including small cell lung cancer and adrenocortical carcinoma (ACC). In ACC, ADCT-701 shows potent activity, but efficacy is reduced by ABCB1-driven drug efflux. DLK1 loss downregulates ABCB1, increases ADC payload and chemotherapy sensitivity via NOTCH1-mediated de-differentiation, and single-cell RNA-seq links DLK low/negative cells to decreased differentiation. These findings support DLK1 ADC targeting in an active phase I trial (NCT06041516) across ACC and neuroendocrine neoplasms.",{"@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":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/identification-of-dlk1-a-notch-ligand-as-an-immunotherapeutic-target-and-regulator-of-tumor-cell-plasticity-and-chemoresistance-in-adrenocortical-carcinoma/331424/",{"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/identification-of-dlk1-a-notch-ligand-as-an-immunotherapeutic-target-and-regulator-of-tumor-cell-plasticity-and-chemoresistance-in-adrenocortical-carcinoma/331424.png","ImageObject",300,407,{"name":92,"@type":93},"River Wang","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-27","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":24},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is the main focus of this study?","Question",{"text":112,"@type":113},"The study identifies DLK1 as an immunotherapeutic cell-surface target and examines how it regulates tumor cell plasticity and chemoresistance in adrenocortical carcinoma (ACC).","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does ADCT-701 perform in ACC and why is efficacy limited?",{"text":117,"@type":113},"ADCT-701 shows potent in vitro and in vivo anti-tumor activity in ACC models; however, its overall efficacy is limited due to high expression and activity of the drug efflux protein ABCB1 (MDR1/P-glycoprotein).",{"name":119,"@type":110,"acceptedAnswer":120},"What happens when DLK1 is genetically deleted in ACC?",{"text":121,"@type":113},"Genetic deletion of DLK1 dramatically downregulates ABCB1 and increases ADC payload delivery and chemotherapy sensitivity through NOTCH1-mediated adrenocortical de-differentiation.","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},331424,1790725685,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":24,"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,"preview_page_count":4},1099514067438,"https://ap-avatar.wpscdn.com/avatar/100002539ee87300030?x-image-process=image/resize,m_fixed,w_180,h_180&k=1780474512215547542","bioRxiv preprint doi: [https://doi.org/10.1101/2024.10.09.617077](https://doi.org/10.1101/2024.10.09.617077); this version posted October 11, 2024. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. This article is a US Government work. It is not subject to copyright under 17 USC  \n105 and is also made available for use under a CC0 license.  \n1 Identification of DLK1, a Notch ligand, as an immunotherapeutic target and regulator of  \n2 tumor cell plasticity and chemoresistance in adrenocortical carcinoma 3  \n4 Nai-Yun Sun1 , Suresh Kumar1 , Yoo Sun Kim1 , Diana Varghese1 , Arnulfo Mendoza2 , Rosa  \n5 Nguyen2 , Reona Okada2 , Karlyne Reilly2 , Brigitte Widemann2 , Yves Pommier 1 , Fathi Elloumi1 , 6 Anjali Dhall1 , Mayank Patel3 , Etan Aber2 , Cristie Contreras-Burrola2 , Rosie Kaplan2 , Dan  \n7 Martinez4 , Jennifer Pogoriler4 , Amber K. Hamilton5 , Sharon J. Diskin5 , John M. Maris5 , Robert  \n8 W. Robey6 , Michael M. Gottesman6 , Jaydira Del Rivero1 and Nitin Roper1\\#  \n9 1 Developmental Therapeutics Branch, Center for Cancer Research, NCI, Bethesda, MD, USA 10 2 Pediatric Oncology Branch, Center for Cancer Research, NCI, Bethesda, MD, USA  \n11 3 Laboratory of Pathology, Center for Cancer Research, NCI, Bethesda, MD, USA  \n12 4 Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia and  \n13 Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA.  \n14 5 Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, and  \n15 Children’s Hospital of Philadelphia, Philadelphia, PA, USA.  \n16 6 Laboratory of Cell Biology, Center for Cancer Research, NCI, Bethesda, MD, USA 17  \n18 \\#Corresponding author:  \n19 Nitin Roper M. D. , M.Sc.  \n20 Investigator  \n21 Lasker Clinical Research Scholar  \n22 Developmental Therapeutics Branch  \n23 Center for Cancer Research  \n24 National Cancer Institute  \n25 37 Convent Drive  \n26 Building 37, Room 5056B  \n27 Bethesda, MD 20892  \n28 Phone: 240-858-3571  \n29 Email: [nitin.roper@nih.gov](nitin.roper@nih.gov)  \n30  \n31  \n32 Funding Sources: NIH Intramural Research Program, NCI, Center for Cancer Research; ADC  \n33 Therapeutics (NR and JDR); Department of Defense Rare Cancers Research Program Concept  \n34 Award (NR); the Cancer Moonshot (ZIA BC0118542) funding to My Pediatric and Adult Rare  \n35 Tumor Network (MyPART) 36  \n37 Competing interests: Nitin Roper and Jaydira Del Rivero have received research funding from  \n38 ADC Therapeutics for this study. The other authors have no competing interests to report. 39  \nbioRxiv preprint doi: [https://doi.org/10.1101/2024.10.09.617077](https://doi.org/10.1101/2024.10.09.617077); this version posted October 11, 2024. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. This article is a US Government work. It is not subject to copyright under 17 USC  \n105 and is also made available for use under a CC0 license.  \n40 Abstract  \n41 Immunotherapeutic targeting of cell surface proteins is an increasingly effective cancer  \n42 therapy. However, given the limited number of current targets, the identification of new surface  \n43 proteins, particularly those with biological importance , is critical. Here, we uncover delta-like non- 44 canonical Notch ligand 1 (DLK1) as a cell surface protein with limited normal tissue expression  \n45 and high expression in multiple refractory adult metastatic cancers including small cell lung cancer  \n46 (SCLC) and adrenocortical carcinoma (ACC) , a rare cancer with few effective therapies. In ACC, 47 ADCT-701, a DLK1 targeting antibody-drug conjugate (ADC) , shows potent in vitro activity among  \n48 established cell lines and a new cohort of patient-derived organoids as well as robust in vivo anti- 49 tumor responses in cell line-derived and patient-derived xenografts. However, ADCT-701 efficacy  \n50 is overall limited in ACC due to high expression and activi","cbCaiqkpMcrQRlcV","https://ap.wps.com/l/cbCaiqkpMcrQRlcV","pdf",4434563,38,"English","# Abstract\n# Introduction","[{\"question\":\"What is the main focus of this study?\",\"answer\":\"The study identifies DLK1 as an immunotherapeutic cell-surface target and examines how it regulates tumor cell plasticity and chemoresistance in adrenocortical carcinoma (ACC).\"},{\"question\":\"How does ADCT-701 perform in ACC and why is efficacy limited?\",\"answer\":\"ADCT-701 shows potent in vitro and in vivo anti-tumor activity in ACC models; however, its overall efficacy is limited due to high expression and activity of the drug efflux protein ABCB1 (MDR1/P-glycoprotein).\"},{\"question\":\"What happens when DLK1 is genetically deleted in ACC?\",\"answer\":\"Genetic deletion of DLK1 dramatically downregulates ABCB1 and increases ADC payload delivery and chemotherapy sensitivity through NOTCH1-mediated adrenocortical de-differentiation.\"}]","Identification of DLK1, a Notch ligand, as an immunotherapeutic target and regulator of tumor cell plasticity and chemoresistance in adrenocortical carcinoma | PDF",1789993217,96]