[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-341160-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-341160-en":130},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","de-novo-purine-metabolism-is-a-metabolic-vulnerability-of-cancers-with-low-p16-expression","De Novo Purine Metabolism is a Metabolic Vulnerability of Cancers with Low p16 Expression","","p16 is a tumor suppressor frequently lost in human cancers, yet its broader impact on nucleotide metabolism and therapy targets remains unclear. Using CRISPR knockout libraries in isogenic melanoma cells, researchers identify nucleotide metabolism genes essential for survival after p16/CDKN2A loss. Many hits increase in melanoma with p16 knockdown or low endogenous CDKN2A. Low p16/CDKN2A cells show sensitivity to de novo purine synthesis inhibitors, including antifolates. In vivo, p16 knockdown tumors respond more strongly to methotrexate, suggesting improved patient selection for these agents.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/de-novo-purine-metabolism-is-a-metabolic-vulnerability-of-cancers-with-low-p16-expression/341160/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/de-novo-purine-metabolism-is-a-metabolic-vulnerability-of-cancers-with-low-p16-expression/341160.png","ImageObject",300,407,{"name":42,"@type":43},"Eliana","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-28","2026-09-22",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",7,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"How is p16 related to tumor development and why is it important in this study?","Question",{"text":63,"@type":64},"p16 is a tumor suppressor that is lost in about half of human cancers. The study focuses on how p16 loss reshapes nucleotide metabolism and creates therapeutic vulnerabilities.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"What experimental approach identifies metabolic dependencies after p16/CDKN2A loss?",{"text":68,"@type":64},"CRISPR knockout libraries were used in isogenic human and mouse melanoma cell lines to determine nucleotide metabolism genes essential for survival with p16/CDKN2A loss.",{"name":70,"@type":61,"acceptedAnswer":71},"Which therapies show enhanced effectiveness in tumors with low p16/CDKN2A expression?",{"text":72,"@type":64},"Cells with low p16/CDKN2A expression are sensitive to multiple de novo purine synthesis inhibitors, including antifolates. Tumors with p16 knockdown are more sensitive to methotrexate in vivo.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},341160,1790120618,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,109,114,119,122,126],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":93,"show_sort_weight":94,"slug":95},"Exam",70,"exam",{"id":97,"doc_module":4,"doc_module_name":25,"category_name":98,"show_sort_weight":99,"slug":100},5,"Comic",60,"comic",{"id":102,"doc_module":4,"doc_module_name":25,"category_name":103,"show_sort_weight":104,"slug":105},6,"Technology",50,"technology",{"id":55,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":107,"slug":108},40,"healthcare",{"id":110,"doc_module":4,"doc_module_name":25,"category_name":111,"show_sort_weight":112,"slug":113},8,"Research & Report",30,"research-report",{"id":115,"doc_module":4,"doc_module_name":25,"category_name":116,"show_sort_weight":117,"slug":118},9,"Religion & Spirituality",20,"religion-spirituality",{"id":117,"doc_module":4,"doc_module_name":25,"category_name":120,"show_sort_weight":117,"slug":121},"World Cup","world-cup",{"id":123,"doc_module":4,"doc_module_name":25,"category_name":124,"show_sort_weight":123,"slug":125},10,"Lifestyle","lifestyle",{"id":127,"doc_module":4,"doc_module_name":25,"category_name":128,"show_sort_weight":97,"slug":129},19,"General","general",{"code":4,"msg":82,"data":131},{"doc_id":79,"user_id":132,"nickname":42,"user_avatar":133,"doc_module":4,"category_id":55,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":139,"language":140,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":12,"update_tm":144,"read_time":145},4398048949847,"https://ap-avatar.wpscdn.com/avatar/400002536579ef2da7f?_k=1778318612642679267","RESEARCH ARTICLE  [https://doi.org/10.1158/2767-9764.CRC-23-0450](https://doi.org/10.1158/2767-9764.CRC-23-0450)  OPEN ACCESS  \nDe Novo Purine Metabolism is a Metabolic Vulnerability of Cancers with Low p16 Expression  \nNaveen Kumar Tangudu1 , Raquel Buj1 , Hui Wang1 , Jiefei Wang2 , Aidan R. Cole1 , Apoorva Uboveja1 , Richard Fang1 , Amandine Amalric1 , Baixue Yang1 , 3 , Adam Chatoff4 , Claudia V. Crispim4 , Peter Sajjakulnukit5 , Maureen A. Lyons6 , Kristine Cooper7 , Nadine Hempel8 , Costas A. Lyssiotis5 , Uma R. Chandran2 , Nathaniel W. Snyder4 , and Katherine M. Aird1  \nCheck for updates  \nABSTRACT  \np16 is a tumor suppressor encoded by the CDKN􀀂A gene whose expression is lost in approximately 50% of all human cancers. In its canonical role, p16 inhibits the G1–S-phase cell cycle progression through suppression of cyclin-dependent kinases. Interestingly, p16 also has roles in metabolic reprogramming, and we previously published that loss of p16 promotes nucleotide synthesis via the pentose phosphate pathway. However, the broader impact of p16/CDKN􀀂A loss on other nucleotide metabolic pathways and potential therapeutic targets remains unexplored. Using CRISPR knockout libraries in isogenic human and mouse melanoma cell lines, we determined several nucleotide metabolism genes essential for the survival of cells with loss of p16/CDKN􀀂A. Consistently, many of these genes are upregulated in melanoma cells with p16 knockdown or endogenously low CDKN􀀂A  \nexpression. We determined that cells with low p16/CDKN􀀂A expression are sensitive to multiple inhibitors of de novo purine synthesis, including antifolates. Finally, tumors with p16 knockdown were more sensitive to the antifolate methotrexate in vivo than control tumors. Together, our data provide evidence to reevaluate the utility of these drugs in patients with p16/CDKN􀀂Alow tumors as loss of p16/CDKN􀀂A may provide a therapeutic window for these agents.  \nSignificance: Antimetabolites were the first chemotherapies, yet many have failed in the clinic due to toxicity and poor patient selection. Our data suggest that p16 loss provides a therapeutic window to kill cancer cells with widely-used antifolates with relatively little toxicity.  \nIntroduction  \np16, encoded by the CDKN􀀂A gene, is a critical cell cycle regulator that inhibits CDK4/6 (1) . Given its importance in the cell cycle, p16 is a well-known tumor suppressor with approximately 50% of all human tumors showing decreased expression or activity of p16 through a variety of mechanisms, including hypermethylation or deletion of the CDKN􀀂A locus or mutations (2–4) . While the CDKN􀀂A gene encodes both p16 and p14, cancer-associated mutations are more commonly found in the p16open reading frame(5, 6), suggesting a more  \n1 Department of Pharmacology and Chemical Biology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.  \n2 Department of Biomedical Informatics and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. 3 Tsinghua University School of Medicine, Beijing, P. R. China. 4 Department of Cardiovascular Sciences, Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania. 5 Department of Molecular and Integrative Physiology, Department of Internal Medicine, Division of Gastroenterology, and Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan. 6 Genomics Facility, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. 7 Biostatistics Facility, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania.  \ncritical regulatory role of p16 in cancer. In melanoma, approximately 30% of patients have a deep deletion of the CDKN􀀂A locus and 10%–15% have CDKN􀀂A mutations (7) . In spite of this high prevalence, there are currently no FDAapproved therapies specifically tailored for these patients. How","cbCaiaXnCu1FQzHt","https://ap.wps.com/l/cbCaiaXnCu1FQzHt","pdf",5898876,15,"English","# Abstract\n# Significance\n# Introduction","[{\"question\":\"How is p16 related to tumor development and why is it important in this study?\",\"answer\":\"p16 is a tumor suppressor that is lost in about half of human cancers. The study focuses on how p16 loss reshapes nucleotide metabolism and creates therapeutic vulnerabilities.\"},{\"question\":\"What experimental approach identifies metabolic dependencies after p16/CDKN2A loss?\",\"answer\":\"CRISPR knockout libraries were used in isogenic human and mouse melanoma cell lines to determine nucleotide metabolism genes essential for survival with p16/CDKN2A loss.\"},{\"question\":\"Which therapies show enhanced effectiveness in tumors with low p16/CDKN2A expression?\",\"answer\":\"Cells with low p16/CDKN2A expression are sensitive to multiple de novo purine synthesis inhibitors, including antifolates. Tumors with p16 knockdown are more sensitive to methotrexate in vivo.\"}]","De Novo Purine Metabolism is a Metabolic Vulnerability of Cancers with Low p16 Expression | PDF",1790040615,38]