[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-detail-354005-en":3,"detail-sidebar-cat-0-en-105":31,"doc-seo-354005-105":81},{"code":4,"msg":5,"data":6},0,"success",{"doc_id":7,"user_id":8,"nickname":9,"user_avatar":10,"doc_module":4,"category_id":11,"category_name":12,"doc_title":13,"doc_description":14,"doc_content":15,"file_id":16,"file_url":17,"file_type":18,"file_size":19,"view_count":20,"is_deleted":4,"is_public":21,"is_downloadable":21,"audit_status":21,"page_count":22,"language":23,"language_code":24,"site_id":25,"html_lang":24,"table_of_contents":26,"faqs":27,"seo_title":28,"seo_description":14,"update_tm":29,"read_time":30},354005,1099523882182,"Alex Sinclair","https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8",7,"Healthcare","Tumor metabolic adaptation induced by L-asparaginase reveals a vulnerability to PARP1/2 inhibitor in B-cell lymphomas","Secondary resistance to the amino-acid–depleting drug L-asparaginase (ASNase) remains poorly understood. Using ASNase-sensitive B-cell lymphoma models, the study examines tumor relapse during treatment. Metabolic profiling shows ASNase triggers metabolic reprogramming with increased de novo serine biosynthesis via PHGDH, reducing oxidative stress and DNA damage to permit malignant survival. The work identifies replication-stress features and elevated PARP activity, and demonstrates that combining ASNase with olaparib enhances antineoplastic effects in vitro and in vivo.","Article [https://doi.org/10.1038/s41467-026-70066-2](https://doi.org/10.1038/s41467-026-70066-2)  \nTumor metabolic adaptation induced by L-asparaginase reveals a vulnerability to PARP1/2 inhibitor in B-cell lymphomas  \nReceived: 30 August 2024  \n\n| Accepted: 11 February 2026 |\n| --- |\n| |\n| Check for updates |\n\nAnaïs Aussel1,2, Ivan Nemazanyy 3, Ashaina Vandenberghe1,2, Pauline Meola1,2, Noémie Dorat1,2, Rachel Paul1,2, Lama Habbouche1, Laurie Exposito1,2,  \nNicolas Nottet1,2, Virginie Petrilli 4, Edmond Chiche1,2,5, Nicolas Mounier1,2,5, Sandrine Marchetti 1,2, Cédric Chaveroux6, Jean-Ehrland Ricci 1,2,7  & Johanna Chiche 1,2,7   \nSecondary resistance to the amino-acid–depleting agent L-asparaginase (ASNase)remains poorly understood. Using ASNase-sensitive B-cell lymphoma (BCL) models, we investigate tumor relapse during treatment. Through in vitro and in vivo metabolic profiling, here we show thatASNase triggers a metabolic reprogramming characterized by increased de novo serine biosynthesis driven by phosphoglycerate dehydrogenase (PHGDH). This response mitigates treatment-induced oxidative stress and associated DNA damage, enabling malignant cells to survive. We evidence that ASNase-treated malignant cells exhibit features of replication stress and increase activity of poly(ADP-ribose) polymerase (PARP), revealing a dependence on DNA repair. Combining ASNase with the clinically approved PARP inhibitor Olaparib enhances the antineoplastic effect of each monotherapy in vitro and in vivo. Moreover, this combination shows effectiveness in homologous recombination-proficient colorectal cancer cells, suggesting broader therapeutic potential. Overall, our study identifies tumor metabolic and genomic vulnerabilities induced by ASNase and supports a rational combination strategy using clinically approved drugs.  \nCancer cells exhibit enhanced metabolism to meet expanding energetic and biosynthetic demands, a vulnerability that prompted several laboratories to develop metabolic inhibitors for clinical use in oncology1–3. Despite successful evaluations on preclinical models of cancers, only a few of these inhibitors have achieved FDA approval, due in part to significant toxicities and development of resistance mechanisms1,4. The intrinsic mechanisms by which tumor cells adapt to metabolic targeting in vivo remain poorly understood, thereby  \nlimiting the development of additional therapeutic strategies for patients who exhibit resistance to routinely used anti-metabolic agents in the clinic.  \nL-asparaginase (ASNase) is the only clinically approved drug targeting cancer cell addiction for a particular amino acid, successfully integrated into multi-agent chemotherapy regimens to treat both childhood and adult T-cell and B-cell acute lymphoblastic leukemias (T-ALL, B-ALL) and NK/T-cell lymphomas (NKTCL) . By catalyzing the  \n1Université Côte d’Azur, INSERM, Nice, France. 2Équipe labellisée LIGUE Contre le Cancer, Nice, France. 3Platform for Metabolic Analyses, Structure Federative de Recherche Necker, INSERM US24/CNRS, Paris, France. 4Université de Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS UMR5286, Centre Léon Bérard CRCL, Lyon, France. 5Centre Hospitalier Universitaire de Nice, Département d’Onco-Hématologie, Nice, France. 6Laboratoire de Biologie Tissulaire et Ingénierie Thérapeutique (LBTI), UMR CNRS 5305, Institut de Biologie et Chimie des Protéines, Université Claude Bernard Lyon 1, Lyon, France. 7These authors contributed equally: Jean-Ehrland Ricci, Johanna Chiche. e-mail: [ricci@unice.fr](ricci@unice.fr); [johanna.chiche@univ-cotedazur.fr](johanna.chiche@univ-cotedazur.fr)  \nhydrolysis of the non-essential amino acid asparagine in the bloodstream, ASNase triggers starvation and selective apoptosis of asparagine-addicted cancer cells. To date, clinical use of ASNase is restricted to ALL and NKTCL, as these hematological malignancies commonly harbor an epigenetic silencing of the gene encoding the asparagine syntheta","cbCaif8W3ElQ8SDs","https://ap.wps.com/l/cbCaif8W3ElQ8SDs","pdf",3949308,8,1,21,"English","en",105,"# Background\n## ASNase and metabolic vulnerabilities in cancer\n# Mechanistic Findings\n## Metabolic reprogramming and serine biosynthesis\n## Oxidative stress, DNA damage, and replication stress\n# Therapeutic Implications\n## PARP dependence after ASNase treatment\n## Synergy with olaparib and broader relevance","[{\"question\":\"What metabolic change does ASNase induce in B-cell lymphoma cells?\",\"answer\":\"ASNase triggers metabolic reprogramming characterized by increased de novo serine biosynthesis driven by PHGDH.\"},{\"question\":\"How does the PHGDH-driven response affect treatment outcomes?\",\"answer\":\"The response mitigates treatment-induced oxidative stress and associated DNA damage, enabling malignant cells to survive.\"},{\"question\":\"Why is combining ASNase with PARP inhibition beneficial?\",\"answer\":\"ASNase-treated malignant cells show replication stress and increased PARP activity, revealing dependence on DNA repair; pairing ASNase with olaparib enhances antineoplastic effects.\"}]","Tumor metabolic adaptation induced by L-asparaginase reveals a vulnerability to PARP1/2 inhibitor in B-cell lymphomas | PDF",1790108434,53,{"code":4,"msg":5,"data":32},[33,38,43,48,53,58,61,65,70,73,77],{"id":21,"doc_module":4,"doc_module_name":34,"category_name":35,"show_sort_weight":36,"slug":37},"Document","Story & Novel",90,"story-novel",{"id":39,"doc_module":4,"doc_module_name":34,"category_name":40,"show_sort_weight":41,"slug":42},2,"Literature",80,"literature",{"id":44,"doc_module":4,"doc_module_name":34,"category_name":45,"show_sort_weight":46,"slug":47},4,"Exam",70,"exam",{"id":49,"doc_module":4,"doc_module_name":34,"category_name":50,"show_sort_weight":51,"slug":52},5,"Comic",60,"comic",{"id":54,"doc_module":4,"doc_module_name":34,"category_name":55,"show_sort_weight":56,"slug":57},6,"Technology",50,"technology",{"id":11,"doc_module":4,"doc_module_name":34,"category_name":12,"show_sort_weight":59,"slug":60},40,"healthcare",{"id":20,"doc_module":4,"doc_module_name":34,"category_name":62,"show_sort_weight":63,"slug":64},"Research & Report",30,"research-report",{"id":66,"doc_module":4,"doc_module_name":34,"category_name":67,"show_sort_weight":68,"slug":69},9,"Religion & Spirituality",20,"religion-spirituality",{"id":68,"doc_module":4,"doc_module_name":34,"category_name":71,"show_sort_weight":68,"slug":72},"World Cup","world-cup",{"id":74,"doc_module":4,"doc_module_name":34,"category_name":75,"show_sort_weight":74,"slug":76},10,"Lifestyle","lifestyle",{"id":78,"doc_module":4,"doc_module_name":34,"category_name":79,"show_sort_weight":49,"slug":80},19,"General","general",{"code":4,"msg":82,"data":83},"ok",{"site_id":25,"language":24,"slug":84,"title":13,"keywords":85,"description":14,"schema_data":86,"social_meta":140,"head_meta":142,"extra_data":144,"updated_unix":145},"tumor-metabolic-adaptation-induced-by-l-asparaginase-reveals-a-vulnerability-to-parp12-inhibitor-in-b-cell-lymphomas","",{"@graph":87,"@context":139},[88,102,122],{"@type":89,"itemListElement":90},"BreadcrumbList",[91,95,97,100],{"item":92,"name":93,"@type":94,"position":21},"https://docshare.wps.com","Home","ListItem",{"item":96,"name":34,"@type":94,"position":39},"https://docshare.wps.com/document/",{"item":98,"name":12,"@type":94,"position":99},"https://docshare.wps.com/document/healthcare/",3,{"item":101,"name":13,"@type":94,"position":44},"https://docshare.wps.com/document/tumor-metabolic-adaptation-induced-by-l-asparaginase-reveals-a-vulnerability-to-parp12-inhibitor-in-b-cell-lymphomas/354005/",{"url":101,"name":13,"@type":103,"image":104,"author":109,"headline":13,"publisher":111,"fileFormat":114,"inLanguage":24,"description":14,"dateModified":115,"datePublished":116,"encodingFormat":114,"isAccessibleForFree":117,"interactionStatistic":118},"DigitalDocument",{"url":105,"@type":106,"width":107,"height":108},"https://docshare.wps.com/thumbnails/tumor-metabolic-adaptation-induced-by-l-asparaginase-reveals-a-vulnerability-to-parp12-inhibitor-in-b-cell-lymphomas/354005.png","ImageObject",300,407,{"name":9,"@type":110},"Person",{"url":92,"name":112,"@type":113},"DocShare","Organization","application/pdf","2026-10-23","2026-09-22",true,{"@type":119,"interactionType":120,"userInteractionCount":20},"InteractionCounter",{"@type":121},"ViewAction",{"@type":123,"mainEntity":124},"FAQPage",[125,131,135],{"name":126,"@type":127,"acceptedAnswer":128},"What metabolic change does ASNase induce in B-cell lymphoma cells?","Question",{"text":129,"@type":130},"ASNase triggers metabolic reprogramming characterized by increased de novo serine biosynthesis driven by PHGDH.","Answer",{"name":132,"@type":127,"acceptedAnswer":133},"How does the PHGDH-driven response affect treatment outcomes?",{"text":134,"@type":130},"The response mitigates treatment-induced oxidative stress and associated DNA damage, enabling malignant cells to survive.",{"name":136,"@type":127,"acceptedAnswer":137},"Why is combining ASNase with PARP inhibition beneficial?",{"text":138,"@type":130},"ASNase-treated malignant cells show replication stress and increased PARP activity, revealing dependence on DNA repair; pairing ASNase with olaparib enhances antineoplastic effects.","https://schema.org",{"og:url":101,"og:type":141,"og:title":13,"og:site_name":112,"og:description":14},"article",{"robots":143,"canonical":101},"index,follow",{"doc_id":7,"site_id":25},1790479813]