[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-336376-105":59,"doc-detail-336376-en":130},{"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":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","mechanistic-patterns-and-clinical-implications-of-oncogenic-tyrosine-kinase-fusions-in-human-cancers","Mechanistic patterns and clinical implications of oncogenic tyrosine kinase fusions in human cancers","","Tyrosine kinase (TK) gene fusions drive cancer initiation and can enable resistance to targeted TK inhibitors, yet the reasons recurrent fusion patterns dominate clinically remain unclear. Using Functionally Active Chromosomal Translocation Sequencing (FACTS) with genome-wide fusion sequencing and clonal selection under drug selective pressure, the study links typical TK fusion selection to fusion-partner transcriptional activity and protein stability. Atypical fusions show reduced stability, weaker oncogenic signaling, and diminished responsiveness to TKI therapy, correlating with poorer treatment response. These mechanistic principles guide clinical targeted therapy decisions.",{"@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/mechanistic-patterns-and-clinical-implications-of-oncogenic-tyrosine-kinase-fusions-in-human-cancers/336376/",{"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/mechanistic-patterns-and-clinical-implications-of-oncogenic-tyrosine-kinase-fusions-in-human-cancers/336376.png","ImageObject",300,407,{"name":92,"@type":93},"Violet","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-28","2026-09-21",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 is the FACTS approach used in this study?","Question",{"text":112,"@type":113},"FACTS integrates high-throughput genome-wide gene fusion sequencing with clonal selection under pharmaceutical selective pressure to identify functionally active oncogenic TK fusions.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What determines why typical TK fusions are selected over atypical ones?",{"text":117,"@type":113},"Typical TK fusions are selected by two main determinants: active transcription of the fusion partner genes and protein stability.",{"name":119,"@type":110,"acceptedAnswer":120},"How do atypical TK fusions affect TKI treatment response?",{"text":121,"@type":113},"Atypical TK fusions show reduced downstream oncogenic signaling and protein stability, leading to less responsiveness to TK inhibition and a reduced response in patients to TKI therapies.","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},336376,1790110148,{"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},4398048950312,"https://ap-avatar.wpscdn.com/avatar/400002538284de19e3c?_k=1778320343897328908","Article [https://doi.org/10.1038/s41467-024-49499-0](https://doi.org/10.1038/s41467-024-49499-0)  \nMechanistic patterns and clinical implications of oncogenic tyrosine kinase fusions in human cancers  \nReceived: 8 January 2024  \n\n| Accepted: 4 June 2024 |\n| --- |\n| |\n| Check for updates |\n\nTaek-Chin Cheong 1,7 , Ahram Jang 1,2,7, Qi Wang 1, Giulia C. Leonardi1,3, Biagio Ricciuti4, Joao V. Alessi4, Alessandro Di Federico4, Mark M. Awad4, Maria K. Lehtinen 1, Marian H. Harris 1 & Roberto Chiarle 1,5,6   \nTyrosine kinase (TK) fusions are frequently found in cancers, either as initiating events or as a mechanism of resistance to targeted therapy. Partner genes and exons in most TK fusions are followed typical recurrent patterns, but the underlying mechanisms and clinical implications of these patterns are poorly understood. By developing Functionally Active Chromosomal Translocation Sequencing (FACTS), we discover that typical TK fusions involving ALK, ROS1, RET and NTRK1 are selected from pools of chromosomal rearrangements by two major determinants: active transcription of the fusion partner genes and protein stability. In contrast, atypical TK fusions that are rarely seen in patients showed reduced protein stability, decreased downstream oncogenic signaling, and were less responsive to inhibition. Consistently, patients with atypical TK fusions were associated with a reduced response to TKI therapies. Our findings highlight the principles of oncogenic TK fusion formation and selection in cancers, with clinical implications for guiding targeted therapy.  \nTyrosine kinase (TK) gene fusions are common genetic alterations across the cancer types, including both hematologic and solid cancers. They are one of the earliest genomic events that initiate oncogenesis, as demonstrated in functional models1, as well as in cancer genome studies2–4. Furthermore, acquisition ofTK fusions, such as ALK or RET fusions, have been also reported during targeted therapy in non-small cell lung cancer (NSCLC) and other tumors, as a mechanism of resistance5–9. Identification of the functional TK fusions is crucial in the clinic because small-molecular TK inhibitors are highly effective for patients with cancers harboring these TK fusions, often regardless of the tissue of origin10–12.  \nTK genes typically fuse with a partner gene that provides an active promoter for the fusion gene’s expression and dimerization or oligomerization domains for TK activation through the fused TK domain13. Mechanistically, TK fusions are often formed by genomic rearrangements between two DNA double-strand breaks (DSBs) in introns, leading to the transcription of in-frame chimeric gene products. However, the mechanisms by which these recurrent breakpoints are selected among the large pool of potential fusion combinations remain unclear14. For example, in patients with NSCLC, EML4 is the most frequent partner gene ofALK fusions and CD74 forROS1 fusions. However, EML4-ROS1 or CD74-ALK fusions have not been reported,  \n1Department of Pathology, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA. 2Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA. 3Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy. 4Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. 5Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy. 6Division of Hematopathology, IEO European Institute of Oncology IRCCS, 20141 Milan, Italy. 7These authors contributed equally: Taek-Chin Cheong, Ahram Jang. e-mail: [taekchin.cheong@childrens.harvard.edu](taekchin.cheong@childrens.harvard.edu); [roberto.chiarle@childrens.harvard.edu](roberto.chiarle@childrens.harvard.edu)  \nalthough these fusions can theoretically be functional. Furthermore, multiple introns inALKcan potentially create i","cbCaioeC44vAhS19","https://ap.wps.com/l/cbCaioeC44vAhS19","pdf",3434190,"English","# Background\n## TK fusion formation and clinical relevance\n# Methods\n## Functionally Active Chromosomal Translocation Sequencing (FACTS)\n# Results\n## Characterization of kinase fusions across cancer types\n## Prevalence across tissue types\n# Clinical implications\n## Response to TKI therapies and fusion-type effects","[{\"question\":\"What is the FACTS approach used in this study?\",\"answer\":\"FACTS integrates high-throughput genome-wide gene fusion sequencing with clonal selection under pharmaceutical selective pressure to identify functionally active oncogenic TK fusions.\"},{\"question\":\"What determines why typical TK fusions are selected over atypical ones?\",\"answer\":\"Typical TK fusions are selected by two main determinants: active transcription of the fusion partner genes and protein stability.\"},{\"question\":\"How do atypical TK fusions affect TKI treatment response?\",\"answer\":\"Atypical TK fusions show reduced downstream oncogenic signaling and protein stability, leading to less responsiveness to TK inhibition and a reduced response in patients to TKI therapies.\"}]","Mechanistic patterns and clinical implications of oncogenic tyrosine kinase fusions in human cancers | PDF",1790014779,48]