Discovery of TAS3351, a brain-penetrable fourth-generation EGFR-TKI that overcomes T790M and C797S resistance mutations

Discovery of TAS3351, a brain-penetrable fourth-generation EGFR-TKI that overcomes T790M and C797S resistance mutations | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Discovery of TAS3351, a brain-penetrable fourth-generation EGFR-TKI that overcomes T790M and C797S resistance mutations Hidefumi Kasuga, Yuki Kataoka, Fuyuki Yamamoto, Rei Miyamoto, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6573462/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Activating mutations in the epidermal growth factor receptor (EGFR), particularly exon 19 deletions and L858R mutation, are frequently observed in non-small cell lung cancer (NSCLC) and confer sensitivity to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, resistance mutations such as T790M and C797S lead to refractory to EGFR-TKIs and ultimately to progression of the disease. In addition, brain metastasis often causes disease progression due to reduced drug penetration into the brain. Here, we demonstrate that TAS3351, a novel fourth-generation EGFR-TKI, overcomes resistance due to T790M and C797S mutations while sparing wild-type EGFR activity. Furthermore, TAS3351 is not a substrate of the efflux transporters and exhibits significant brain penetrability, resulting in high efficacy in mouse models with intracranial allografts. These findings indicate that TAS3351 is a promising therapeutic candidate for patients with NSCLC who have relapsed and are refractory to treatment due to C797S and T790M resistance mutations, including those with brain metastases. Biological sciences/Cancer/Cancer therapy/Drug development Biological sciences/Drug discovery/Pharmaceutics Full Text Additional Declarations Yes there is potential Competing Interest. All authors are employee of Taiho Pharmaceutical Co., Ltd. a wholly owned subsidiary of Otsuka Holdings Co., Ltd. Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6573462","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":455807149,"identity":"04e8b460-1f8a-448f-9dff-8d6ec5bdb55f","order_by":0,"name":"Hidefumi Kasuga","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3klEQVRIiWNgGAWjYBACAwY2CIMfiA9DBROI0yLZRrIWg2MMDMxEOcycgS3x48+2Wnnj+80PDxdUMMgDXfjsAT4tlg1sh6V5244bbjvGZnB4xhkGw5kNDOkGeB12/3mDNGPbMcZtxxgMDvO2MSQYHGBIk8Cr5QB788+fbcfsN7exfyBWC9sxCd62msQNbDxE28KWZs1z7kDyjGM5BYd5zkgYzmwm5JcDbMY3f5TV2fY3H9/8mafCRp6fvSftAT4tUACLRAagk5h50ojQwVCHzGE/RoyWUTAKRsEoGDkAAOaDR/bJxpACAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0009-0000-1859-7843","institution":"Taiho Pharmaceutical, Co. Ltd.","correspondingAuthor":true,"prefix":"","firstName":"Hidefumi","middleName":"","lastName":"Kasuga","suffix":""},{"id":455807150,"identity":"fcc60cbc-7dff-4d0a-8e98-79b0df5bae22","order_by":1,"name":"Yuki Kataoka","email":"","orcid":"https://orcid.org/0000-0001-5194-654X","institution":"Taiho Pharmaceutical (Japan)","correspondingAuthor":false,"prefix":"","firstName":"Yuki","middleName":"","lastName":"Kataoka","suffix":""},{"id":455807151,"identity":"5c94a9c5-631f-4f1d-8378-1c3a530d7f74","order_by":2,"name":"Fuyuki Yamamoto","email":"","orcid":"","institution":"Taiho Pharmaceutical, Co. Ltd.","correspondingAuthor":false,"prefix":"","firstName":"Fuyuki","middleName":"","lastName":"Yamamoto","suffix":""},{"id":455807152,"identity":"c7d03f0f-017e-4a91-8e58-fc8dc5bd2daf","order_by":3,"name":"Rei Miyamoto","email":"","orcid":"","institution":"Taiho Pharmaceutical, Co. Ltd.","correspondingAuthor":false,"prefix":"","firstName":"Rei","middleName":"","lastName":"Miyamoto","suffix":""},{"id":455807153,"identity":"5ac5e5d8-6832-421c-b18d-d3fbf9e56a66","order_by":4,"name":"Shingo Tsuji","email":"","orcid":"","institution":"Taiho Pharmaceutical, Co. Ltd.","correspondingAuthor":false,"prefix":"","firstName":"Shingo","middleName":"","lastName":"Tsuji","suffix":""},{"id":455807154,"identity":"897ef121-77c0-4123-ad24-a163cb8132fa","order_by":5,"name":"Tatsuya Suzuki","email":"","orcid":"","institution":"Taiho Pharmaceutical Co Ltd","correspondingAuthor":false,"prefix":"","firstName":"Tatsuya","middleName":"","lastName":"Suzuki","suffix":""},{"id":455807155,"identity":"fb06a7ca-a011-4a5a-8c87-faf1b436a3fd","order_by":6,"name":"Shinji Mizuarai","email":"","orcid":"","institution":"Taiho Pharmaceutical, Co. Ltd.","correspondingAuthor":false,"prefix":"","firstName":"Shinji","middleName":"","lastName":"Mizuarai","suffix":""}],"badges":[],"createdAt":"2025-05-01 17:20:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6573462/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6573462/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83305416,"identity":"eed477a6-9a90-4e1c-9458-d62d4d9a9d58","added_by":"auto","created_at":"2025-05-22 16:20:06","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1194609,"visible":true,"origin":"","legend":"Article File","description":"","filename":"ManuscriptKasugaetal.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6573462/v1_covered_d948d937-40d3-4ceb-a9d6-f9294eb837af.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nAll authors are employee of Taiho Pharmaceutical Co., Ltd. a wholly owned subsidiary of Otsuka Holdings Co., Ltd.","formattedTitle":"Discovery of TAS3351, a brain-penetrable fourth-generation EGFR-TKI that overcomes T790M and C797S resistance mutations","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6573462/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6573462/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Activating mutations in the epidermal growth factor receptor (EGFR), particularly exon 19 deletions and L858R mutation, are frequently observed in non-small cell lung cancer (NSCLC) and confer sensitivity to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, resistance mutations such as T790M and C797S lead to refractory to EGFR-TKIs and ultimately to progression of the disease. In addition, brain metastasis often causes disease progression due to reduced drug penetration into the brain. Here, we demonstrate that TAS3351, a novel fourth-generation EGFR-TKI, overcomes resistance due to T790M and C797S mutations while sparing wild-type EGFR activity. Furthermore, TAS3351 is not a substrate of the efflux transporters and exhibits significant brain penetrability, resulting in high efficacy in mouse models with intracranial allografts. These findings indicate that TAS3351 is a promising therapeutic candidate for patients with NSCLC who have relapsed and are refractory to treatment due to C797S and T790M resistance mutations, including those with brain metastases.","manuscriptTitle":"Discovery of TAS3351, a brain-penetrable fourth-generation EGFR-TKI that overcomes T790M and C797S resistance mutations","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-22 16:11:56","doi":"10.21203/rs.3.rs-6573462/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"communications-medicine","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"commsmed","sideBox":"Learn more about [Communications Medicine](http://www.nature.com/commsmed)","snPcode":"43856","submissionUrl":"https://mts-commsmed.nature.com/cgi-bin/main.plex","title":"Communications Medicine","twitterHandle":"@commsmedicine","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Communications Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"145c430f-32c0-41f4-a822-f2c4a2fa5b3c","owner":[],"postedDate":"May 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":48449631,"name":"Biological sciences/Cancer/Cancer therapy/Drug development"},{"id":48449632,"name":"Biological sciences/Drug discovery/Pharmaceutics"}],"tags":[],"updatedAt":"2025-05-22T16:11:56+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-22 16:11:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6573462","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6573462","identity":"rs-6573462","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}