[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-380504-105":59,"doc-detail-380504-en":131},{"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":124,"head_meta":126,"extra_data":128,"updated_unix":130},105,"en","signature-driven-repurposing-of-midostaurin-for-combination-with-mek12-and-krasg12c-inhibitors-in-lung-cancer","Signature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer","","Signature-driven repurposing is used to uncover combination therapies for KRAS-mutated lung adenocarcinoma. Drug combinations pairing multityrosine kinase PKC inhibitors with MEK1/2 or KRASG12C inhibitors elicit synergistic cytotoxicity in vitro and in vivo, involving inhibition of the AURKB target. Proteome profiling links MYC dysregulation to the combination effects, while MYC overexpression emerges as a resistance mechanism. The study provides a rationale for selecting drugs for combinatorial strategies and advances MEK1/2- and KRASG12C-based options.",{"@graph":69,"@context":123},[70,84,106],{"@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/signature-driven-repurposing-of-midostaurin-for-combination-with-mek12-and-krasg12c-inhibitors-in-lung-cancer/380504/",{"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/signature-driven-repurposing-of-midostaurin-for-combination-with-mek12-and-krasg12c-inhibitors-in-lung-cancer/380504.png","ImageObject",300,407,{"name":92,"@type":93},"Stanley","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",11,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What problem does the study address in targeted lung cancer therapy?","Question",{"text":113,"@type":114},"Targeted therapies often show limited effectiveness due to intrinsic and adaptive resistance, so rational combinatorial treatments are needed for stronger and longer-lasting responses.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"Which drug combinations show synergistic effects in KRAS-mutated LUAD?",{"text":118,"@type":114},"The study identifies combinations of MEK1/2 inhibitors with multityrosine kinase PKC inhibitors, and shows KRASG12C inhibition (with Sotorasib) can substitute for Trametinib with similar efficacy.",{"name":120,"@type":111,"acceptedAnswer":121},"How does the research explain the mechanisms behind the drug combinations and resistance?",{"text":122,"@type":114},"Mechanistic analyses indicate cytotoxic effects involve AURKB inhibition, proteome profiling connects MYC expression dysregulation to combination response, and MYC overexpression can drive resistance to MEK1/2 and KRASG12C inhibitors.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},380504,1790471730,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":56,"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},2336477405376,"https://ap-avatar.wpscdn.com/davatar_29158cc5080c5b710cf443261637dec0","Article [https://doi.org/10.1038/s41467-023-41828-z](https://doi.org/10.1038/s41467-023-41828-z)  \nSignature-driven repurposing ofMidostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer  \nReceived: 13 December 2022  \n\n| Accepted: 20 September 2023 |\n| --- |\n| |\n| Check for updates |\n\nA list of authors and their affiliations appears at the end of the paper  \nDrug combinations are key to circumvent resistance mechanisms compromising response to single anti-cancer targeted therapies. The implementation of combinatorial approaches involving MEK1/2 or KRASG12C inhibitors in the context of KRAS-mutated lung cancers focuses fundamentally on targeting KRAS proximal activators or effectors. However, the antitumor effect is highly determined by compensatory mechanisms arising in defined cell types or tumor subgroups. A potential strategy to find drug combinations targeting a larger fraction of KRAS-mutated lung cancers may capitalize on the common, distal gene expression output elicited by oncogenic KRAS. By integrating a signature-driven drug repurposing approach with a pairwise pharmacological screen, here we show synergistic drug combinations consisting of multityrosine kinase PKC inhibitors together with MEK1/2 or KRASG12C inhibitors. Such combinations elicit a cytotoxic response in both in vitro and in vivo models, which in part involves inhibition of the PKC inhibitor target AURKB. Proteome profiling links dysregulation of MYC expression to the effect of both PKC inhibitor-based drug combinations. Furthermore, MYC overexpression appears as a resistance mechanism to MEK1/2 and KRASG12C inhibitors. Our study provides a rational framework for selecting drugs entering combinatorial strategies and unveils MEK1/2-and KRASG12C-based therapies for lung cancer.  \nTargeted therapies often display limited antitumor effect due to intrinsic and adaptive resistance mechanisms, underscoring the need for rational combinatorial treatments to yield better and more durable responses1,2. Given the relevance of the RAF-MEK-ERK pathway in KRAS-driven lung cancer3, particularly in the most frequently diagnosed subtype, lung adenocarcinoma (LUAD), combinations of MEK1/2 inhibitors (MEKi) with targeted agents to proximal elements of the KRAS signaling network have been reported4–12. Likewise, recent studies using KRASG12C inhibitors (KRASG12Ci) have illustrated the requirement of additional pathway inactivation for deep antitumor responses13–19. Overall, drugs selected for dual strategies have been nominated by previous knowledge on proximal signaling pathways involved in KRAS oncogenesis or in adaptive resistance to  \nMEKi. However, the efficacy of such drug combinations is generally restricted to subsets of mutant (mut) KRAS LUAD with specific signaling pathway activation/reactivation or epithelial/mesenchymal phenotypes7,12,20. An alternative to nominate drugs entering combinatorial approaches whose effect spans a large fraction of patients may capitalize on the common gene expression output originated by KRAS oncoprotein that is featured in LUAD, but is yet to be investigated.  \nDrug repurposing is an effective strategy to find new indications for existing drugs already tested for safety, dosage, and toxicity21. The development of combinatorial approaches that could rapidly progress to the clinic may be expedited by the identification of repurposed drugs. One drug repositioning approach utilizes transcriptional  \ne-mail: [silvevicent@unav.es](silvevicent@unav.es)  \nprofiles generated from cell lines exposed to a large compendium of pharmacological compounds22 and aims to predict drugs that reverse the expression of a gene signature representative of a certain disease23. A successful example of this approach in lung cancer was the identification of tricyclic antidepressants as potential therapeutics for smallcell lung cancer24. However, such drug repurposing strategy has so far not been fully exploited for the development of therapies in l","cbCaikNkvufg4Kr2","https://ap.wps.com/l/cbCaikNkvufg4Kr2","pdf",4600833,"English","# Introduction\n# Results\n## Synergistic drug combinations in mut KRAS LUAD unveiled through a drug repurposing-based strategy","[{\"question\":\"What problem does the study address in targeted lung cancer therapy?\",\"answer\":\"Targeted therapies often show limited effectiveness due to intrinsic and adaptive resistance, so rational combinatorial treatments are needed for stronger and longer-lasting responses.\"},{\"question\":\"Which drug combinations show synergistic effects in KRAS-mutated LUAD?\",\"answer\":\"The study identifies combinations of MEK1/2 inhibitors with multityrosine kinase PKC inhibitors, and shows KRASG12C inhibition (with Sotorasib) can substitute for Trametinib with similar efficacy.\"},{\"question\":\"How does the research explain the mechanisms behind the drug combinations and resistance?\",\"answer\":\"Mechanistic analyses indicate cytotoxic effects involve AURKB inhibition, proteome profiling connects MYC expression dysregulation to combination response, and MYC overexpression can drive resistance to MEK1/2 and KRASG12C inhibitors.\"}]","Signature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer | PDF",1790240458,48]