[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-344854-105":59,"doc-detail-344854-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","synthetic-gene-circuits-that-selectively-target-ras-driven-cancers","Synthetic gene circuits that selectively target RAS-driven cancers","","Therapies targeting mutated RAS address a major driver of human cancer, yet approved inhibitors remain mutation-specific and often limited by resistance. Synthetic gene circuits provide an alternative by sensing cancer-relevant biomolecular inputs and selectively producing therapeutic proteins. A central requirement is high cancer selectivity to avoid harm in healthy cells. The study introduces a multi-sensor strategy combining RAS sensors into RAStargeting circuits, enabling unprecedented selective expression. Modular design and component modeling allow cell-line-specific adaptation to optimize selectivity and tune output.",{"@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/synthetic-gene-circuits-that-selectively-target-ras-driven-cancers/344854/",{"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/synthetic-gene-circuits-that-selectively-target-ras-driven-cancers/344854.png","ImageObject",300,407,{"name":92,"@type":93},"Olivia Brown","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-24","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":8},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What problem do the authors aim to solve in RAS-targeted cancer therapy?","Question",{"text":112,"@type":113},"They address the limited target scope and resistance of current RAS inhibitors, along with the need for strong cancer selectivity to prevent toxicity in healthy cells.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How do the presented synthetic gene circuits achieve selective expression in cancer cells?",{"text":117,"@type":113},"They combine multiple RAS sensors into RAStargeting gene circuits so that output protein expression occurs preferentially in cells carrying mutated RAS.",{"name":119,"@type":110,"acceptedAnswer":120},"What evidence supports the therapeutic potential of the circuits?",{"text":121,"@type":113},"The circuits are tested in different RAS-driven cancer cell lines and linked to expression of a clinically relevant output protein that induces robust killing of cancer cells with mutated RAS.","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},344854,1790217389,{"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":8,"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},16904993612988,"https://ap-avatar.wpscdn.com/davatar_a8503ba1806abce46bf441b54a3ca4cd","RESEARCH ARTICLE  \n*For correspondence:  \n[kobi.benenson@gmail.com](kobi.benenson@gmail.com)[ ](kobi.benenson@gmail.com)[Present address:](Present address:) †Pattern Biosciences, Basel, Switzerland  \nCompeting interest: See page 25  \nFunding: See page 25  \nPreprint posted  \n11 November 2024  \nSent for Review  \n11 November 2024  \nReviewed preprint posted  \n12 February 2025  \nReviewed preprint revised  \n29 September 2025  \nVersion of Record published  \n24 February 2026  \nReviewing Editor: Ahmad S Khalil, Boston University, United States  \n Copyright Senn et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use andredistribution provided that the original author and source are credited.  \nSynthetic gene circuits that selectively target RAS-driven cancers  \nGabriel Valentin Senn, Leon Nissen, Yaakov Benenson*†  \nDepartment of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland  \n\n| eLife Assessment\u003Cbr>This important study demonstrates the potential of synthetic gene circuits to detect and target aberrant RAS activity in cancer cell lines. The circuit design is novel and the evidence supporting the claims is convincing. As a proof-of-concept, this will be of broad interest to researchers in synthetic biology and therapeutics development, while future work will be required to help translate this technology toward clinical applications in cancer therapeutics and address potential limitations of the strategy. |\n| --- |\n| Abstract Therapies targeting mutated rat sarcoma (RAS), the most frequently mutated oncogene in human cancers, could benefit millions of patients. Recently approved RAS inhibitors represent a breakthrough but are limited to a specific KRASG12C mutation and prone to resistance. Synthetic gene circuits offer a promising alternative by sensing and integrating cancer-specific biomolecular inputs, including mutated RAS, to selectively express therapeutic proteins in cancer cells. A key challenge for these circuits is achieving high cancer selectivity to prevent toxicity in healthy cells. To address this challenge, we present a novel approach combining multiple RAS sensors into RAStargeting gene circuits, which allowed us to express an output protein in cells with mutated RAS with unprecedented selectivity. We implemented a modular design strategy and modeled the impact of individual circuit components on output expression. This enabled cell-line-specific adaptation of the circuits to optimize selectivity and fine-tune expression. We further demonstrate the targeting capabilities of the circuits by employing them in different RAS-driven cancer cells and provide evidence for their therapeutic potential by linking them to the expression of a clinically relevant output protein, which induced robust killing of cancer cells with mutated RAS. This work highlights the potential of synthetic gene circuits as a novel therapeutic strategy for RAS-driven cancers, advancing the application of synthetic biology in oncology. |\n\nIntroduction  \nRAS (rat sarcoma) mutations are the most common oncogenic alterations in human cancers (Timarand Kashofer, 2020), accounting for 19% of all cases (Prior et al., 2020) . The RAS gene family consists of HRAS, KRAS, and NRAS, with KRAS being the most frequently mutated isoform (Muñoz-Maldonado et al., 2019) . Considered ‘undruggable’ for many years, recent approval of several KRASG12C inhibitors (Boumelha et al., 2023) has demonstrated the efficacy of targeting RAS in cancer treatment. However, these therapies are limited to cancers with KRASG12C mutations, which narrows the target range and makes the inhibitors susceptible to resistance development due to the emergence of other RAS mutations (Steffen et al., 2023) . While KRASG12C remains the only RAS mutation with approved targeted inhibitors, recent advances have expanded the therapeutic landscape. Several inhibitors targeting other RAS mutations, including KRASG12D","cbCairodJr8DV3k6","https://ap.wps.com/l/cbCairodJr8DV3k6","pdf",5010263,29,"English","# Introduction\n# eLife Assessment\n# Abstract\n## Background: RAS and current inhibitors\n## Circuit strategy and selectivity goals\n## Modular design and evidence of therapeutic potential","[{\"question\":\"What problem do the authors aim to solve in RAS-targeted cancer therapy?\",\"answer\":\"They address the limited target scope and resistance of current RAS inhibitors, along with the need for strong cancer selectivity to prevent toxicity in healthy cells.\"},{\"question\":\"How do the presented synthetic gene circuits achieve selective expression in cancer cells?\",\"answer\":\"They combine multiple RAS sensors into RAStargeting gene circuits so that output protein expression occurs preferentially in cells carrying mutated RAS.\"},{\"question\":\"What evidence supports the therapeutic potential of the circuits?\",\"answer\":\"The circuits are tested in different RAS-driven cancer cell lines and linked to expression of a clinically relevant output protein that induces robust killing of cancer cells with mutated RAS.\"}]","Synthetic gene circuits that selectively target RAS-driven cancers | PDF",1790055468,73]