{"paper_id":"097609e3-6309-4123-9401-339a43cabe1c","body_text":"Cyclin E1/CDK2 Activation Defines a Key Vulnerability to WEE1 Kinase Inhibition in Gynecological Cancers | 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 Help Center Sign In Submit a Preprint Cite Share Download PDF Article Cyclin E1/CDK2 Activation Defines a Key Vulnerability to WEE1 Kinase Inhibition in Gynecological Cancers Jianhui Ma, Daehwan Kim, Heekyung Chung, Wen Liu, Kangjin Jeong, and 24 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4397695/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Jan, 2025 Read the published version in npj Precision Oncology → Version 1 posted 10 You are reading this latest preprint version Abstract Upregulation of Cyclin E1 and subsequent activation of CDK2 accelerates cell-cycle progression from G1 to S phase and is a common oncogenic driver in gynecological malignancies. WEE1 kinase counteracts the effects of Cyclin E1/CDK2 activation by regulating multiple cell cycle checkpoints. Here we characterized the relationship between Cyclin E1/CDK2 activation and sensitivity to the selective WEE1 inhibitor azenosertib. We found that ovarian cancer cell lines with high levels of endogenous Cyclin E1 expression or forced overexpression were exquisitely sensitive to azenosertib and these results extended to in vivo models of ovarian and uterine serous carcinoma. Models with high Cyclin E1 expression showed higher baseline levels of replication stress and enhanced cellular responses to azenosertib treatment. We found azenosertib synergized with different classes of chemotherapy and described distinct underlying mechanisms. Finally, we provided early evidence from an ongoing phase I study demonstrating clinical activity of monotherapy azenosertib in patients with Cyclin E1/CDK2 activated ovarian and uterine serous carcinomas. Biological sciences/Drug discovery/Biomarkers/Predictive markers Biological sciences/Cancer/Cancer therapy/Targeted therapies Full Text Additional Declarations There is a conflict of interest D. Kim is an employee and shareholder of Zentalis Pharmaceuticals. H. Chung is an employee and shareholder of Zentalis Pharmaceuticals. W. Liu is an employee and shareholder of Zentalis Pharmaceuticals. S. Kim is an employee and shareholder of Zentalis Pharmaceuticals. X. Guo is an employee and shareholder of Zentalis Pharmaceuticals. N. Jameson is an employee and shareholder of Zentalis Pharmaceuticals. P.R. de Jong is a former employee of Zentalis Pharmaceuticals. S. Yea is an employee and shareholder of Zentalis Pharmaceuticals. L. Harford is an employee and shareholder of Zentalis Pharmaceuticals. J. Li is a former employee of Zentalis Pharmaceuticals. D. Kim is an employee and shareholder of Zentalis Pharmaceuticals. K. Fischer is an employee and shareholder of Zentalis Pharmaceuticals. A. Samatar is an employee of Zentalis Pharmaceuticals and shareholder in Zentalis Pharmaceuticals. A. Jubb is an employee and shareholder of Zentalis Pharmaceuticals. K. Bunker is an employee of Zentalis Pharmaceuticals and shareholder in Zentalis Pharmaceuticals. K. Blackwell is an employee and shareholder of Zentalis Pharmaceuticals. F. Simpkins serves on scientific advisory boards for AstraZeneca, GSK and Zentalis Pharmaceuticals; has received institutional research funding from AstraZeneca, Repare Therapeutics, Instill Bio and Sierra Oncology. F. Meric-Bernstam is consultant for. AbbVie, Aduro BioTech Inc., Alkermes, AstraZeneca, Daiichi Sankyo Co. Ltd., Calibr (a division of Scripps Research), DebioPharm, Ecor1 Capital, eFFECTOR Therapeutics, Exelixis, F. Hoffman-La Roche Ltd., GT Apeiron, Genentech Inc., Harbinger Health, IBM Watson, Incyte, Infinity Pharmaceuticals, Jackson Laboratory, Jazz Pharmaceuticals, Kolon Life Science, LegoChem Bio, Lengo Therapeutics, Loxo Oncology, Menarini Group, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Protai Bio Ltd, Samsung Bioepis, Seattle Genetics Inc., Tallac Therapeutics, Tyra Biosciences, Xencor, Zymeworks; Advisory Committee for Black Diamond, Biovica, Eisai, FogPharma, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Sanofi, Silverback Therapeutics, Spectrum Pharmaceuticals, Theratechnologies, Zentalis; Received sponsored Research (to the institution) from Jazz Pharmaceuticals, Zymeworks, Aileron Therapeutics, Inc. AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Klus Pharma, Takeda Pharmaceutical, Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co.; Honoraria for Dava Oncology; receiving travel related funding and reimbursement from European Organisation for Research and Treatment of Cancer (EORTC), European Society for Medical Oncology (ESMO), Cholangiocarcinoma Foundation, Dava Oncology. G.B. Mills is scientific advisory board/Consultant for Amphista, Astex, AstraZeneca, BlueDot, Chrysallis Biotechnology, Ellipses Pharma, GSK, ImmunoMET, Infinity, Ionis, Leapfrog Bio, Lilly, Medacorp, Nanostring, Nuvectis, PDX Pharmaceuticals, Qureator, Roche, Signalchem Lifesciences, Tarveda, Turbine, Zentalis Pharmaceuticals; Stock/Options/Financial: Bluedot, Catena Pharmaceuticals, ImmunoMet, Nuvectis, SignalChem, Tarveda, Turbine; Licensed Technology: HRD assay to Myriad Genetics, DSP patents with Nanostring; Sponsored research: AstraZeneca. O. Harismendy is an employee and shareholder of Zentalis Pharmaceuticals. J. Ma is an employee and shareholder of Zentalis Pharmaceuticals. M.R. Lackner is an employee and shareholder of Zentalis Pharmaceuticals. No disclosures were reported by the other authors. Supplementary Files SupplementaryInformation.pdf Cite Share Download PDF Status: Published Journal Publication published 04 Jan, 2025 Read the published version in npj Precision Oncology → Version 1 posted Editorial decision: revise 14 Aug, 2024 Review # 3 received at journal 06 Aug, 2024 Reviewer # 3 agreed at journal 26 Jul, 2024 Reviewer # 2 agreed at journal 26 Jun, 2024 Review # 1 received at journal 07 Jun, 2024 Reviewer # 1 agreed at journal 30 May, 2024 Reviewers invited by journal 29 May, 2024 Editor assigned by journal 13 May, 2024 Submission checks completed at journal 10 May, 2024 First submitted to journal 09 May, 2024 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. 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Also discoverable on Platform About Our Team In Review Editorial Policies 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-4397695\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Article\",\"associatedPublications\":[],\"authors\":[{\"id\":308355673,\"identity\":\"bd05cb2e-535c-42bf-9891-6412150034ef\",\"order_by\":0,\"name\":\"Jianhui 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Kim is an employee and shareholder of Zentalis Pharmaceuticals. H. Chung is an employee and shareholder of Zentalis Pharmaceuticals. W. Liu is an employee and shareholder of Zentalis Pharmaceuticals. S. Kim is an employee and shareholder of Zentalis Pharmaceuticals. X. Guo is an employee and shareholder of Zentalis Pharmaceuticals. N. Jameson is an employee and shareholder of Zentalis Pharmaceuticals. P.R. de Jong is a former employee of Zentalis Pharmaceuticals. S. Yea is an employee and shareholder of Zentalis Pharmaceuticals. L. Harford is an employee and shareholder of Zentalis Pharmaceuticals. J. Li is a former employee of Zentalis Pharmaceuticals. D. Kim is an employee and shareholder of Zentalis Pharmaceuticals. K. Fischer is an employee and shareholder of Zentalis Pharmaceuticals. A. Samatar is an employee of Zentalis Pharmaceuticals and shareholder in Zentalis Pharmaceuticals. A. Jubb is an employee and shareholder of Zentalis Pharmaceuticals. K. Bunker is an employee of Zentalis Pharmaceuticals and shareholder in Zentalis Pharmaceuticals. K. Blackwell is an employee and shareholder of Zentalis Pharmaceuticals. F. Simpkins serves on scientific advisory boards for AstraZeneca, GSK and Zentalis Pharmaceuticals; has received institutional research funding from AstraZeneca, Repare Therapeutics, Instill Bio and Sierra Oncology. F. Meric-Bernstam is consultant for. AbbVie, Aduro BioTech Inc., Alkermes, AstraZeneca, Daiichi Sankyo Co. Ltd., Calibr (a division of Scripps Research), DebioPharm, Ecor1 Capital, eFFECTOR Therapeutics, Exelixis, F. Hoffman-La Roche Ltd., GT Apeiron, Genentech Inc., Harbinger Health, IBM Watson, Incyte, Infinity Pharmaceuticals, Jackson Laboratory, Jazz Pharmaceuticals, Kolon Life Science, LegoChem Bio, Lengo Therapeutics, Loxo Oncology, Menarini Group, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Protai Bio Ltd, Samsung Bioepis, Seattle Genetics Inc., Tallac Therapeutics, Tyra Biosciences, Xencor, Zymeworks; Advisory Committee for Black Diamond, Biovica, Eisai, FogPharma, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Sanofi, Silverback Therapeutics, Spectrum Pharmaceuticals, Theratechnologies, Zentalis; Received sponsored Research (to the institution) from Jazz Pharmaceuticals, Zymeworks, Aileron Therapeutics, Inc. AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Klus Pharma, Takeda Pharmaceutical, Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co.; Honoraria for Dava Oncology; receiving travel related funding and reimbursement from European Organisation for Research and Treatment of Cancer (EORTC), European Society for Medical Oncology (ESMO), Cholangiocarcinoma Foundation, Dava Oncology. G.B. Mills is scientific advisory board/Consultant for Amphista, Astex, AstraZeneca, BlueDot, Chrysallis Biotechnology, Ellipses Pharma, GSK, ImmunoMET, Infinity, Ionis, Leapfrog Bio, Lilly, Medacorp, Nanostring, Nuvectis, PDX Pharmaceuticals, Qureator, Roche, Signalchem Lifesciences, Tarveda, Turbine, Zentalis Pharmaceuticals; Stock/Options/Financial: Bluedot, Catena Pharmaceuticals, ImmunoMet, Nuvectis, SignalChem, Tarveda, Turbine; Licensed Technology: HRD assay to Myriad Genetics, DSP patents with Nanostring; Sponsored research: AstraZeneca. O. Harismendy is an employee and shareholder of Zentalis Pharmaceuticals. J. Ma is an employee and shareholder of Zentalis Pharmaceuticals. M.R. Lackner is an employee and shareholder of Zentalis Pharmaceuticals. No disclosures were reported by the other authors.\",\"formattedTitle\":\"Cyclin E1/CDK2 Activation Defines a Key Vulnerability to WEE1 Kinase Inhibition in Gynecological Cancers\",\"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\":\"info@researchsquare.com\",\"identity\":\"npj-precision-oncology\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"npjprecisiononcology\",\"sideBox\":\"Learn more about [npj Precision Oncology](http://www.nature.com/npjprecisiononcology/)\",\"snPcode\":\"41698\",\"submissionUrl\":\"https://submission.springernature.com/new-submission/41698/3\",\"title\":\"npj Precision Oncology\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"stoa\",\"reportingPortfolio\":\"NPJ\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true},\"keywords\":\"\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-4397695/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-4397695/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"Upregulation of Cyclin E1 and subsequent activation of CDK2 accelerates cell-cycle progression from G1 to S phase and is a common oncogenic driver in gynecological malignancies. WEE1 kinase counteracts the effects of Cyclin E1/CDK2 activation by regulating multiple cell cycle checkpoints. Here we characterized the relationship between Cyclin E1/CDK2 activation and sensitivity to the selective WEE1 inhibitor azenosertib. We found that ovarian cancer cell lines with high levels of endogenous Cyclin E1 expression or forced overexpression were exquisitely sensitive to azenosertib and these results extended to in vivo models of ovarian and uterine serous carcinoma. Models with high Cyclin E1 expression showed higher baseline levels of replication stress and enhanced cellular responses to azenosertib treatment. We found azenosertib synergized with different classes of chemotherapy and described distinct underlying mechanisms. Finally, we provided early evidence from an ongoing phase I study demonstrating clinical activity of monotherapy azenosertib in patients with Cyclin E1/CDK2 activated ovarian and uterine serous carcinomas.\",\"manuscriptTitle\":\"Cyclin E1/CDK2 Activation Defines a Key Vulnerability to WEE1 Kinase Inhibition in Gynecological Cancers\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2024-06-12 04:53:06\",\"doi\":\"10.21203/rs.3.rs-4397695/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"revise\",\"date\":\"2024-08-14T11:26:08+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"This content is not available.\",\"date\":\"2024-08-06T19:34:13+00:00\",\"index\":3,\"fulltext\":\"This content is not available.\"},{\"type\":\"reviewerAgreed\",\"content\":\"This content is not available.\",\"date\":\"2024-07-26T19:17:10+00:00\",\"index\":3,\"fulltext\":\"This content is not available.\"},{\"type\":\"reviewerAgreed\",\"content\":\"This content is not available.\",\"date\":\"2024-06-26T17:20:32+00:00\",\"index\":2,\"fulltext\":\"This content is not available.\"},{\"type\":\"editorInvitedReview\",\"content\":\"This content is not available.\",\"date\":\"2024-06-07T08:34:39+00:00\",\"index\":1,\"fulltext\":\"This content is not available.\"},{\"type\":\"reviewerAgreed\",\"content\":\"This content is not available.\",\"date\":\"2024-05-30T04:29:23+00:00\",\"index\":1,\"fulltext\":\"This content is not available.\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2024-05-29T18:55:58+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2024-05-14T02:46:34+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2024-05-10T06:55:02+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"npj Precision Oncology\",\"date\":\"2024-05-10T02:21:40+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"npj-precision-oncology\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"npjprecisiononcology\",\"sideBox\":\"Learn more about [npj Precision Oncology](http://www.nature.com/npjprecisiononcology/)\",\"snPcode\":\"41698\",\"submissionUrl\":\"https://submission.springernature.com/new-submission/41698/3\",\"title\":\"npj Precision Oncology\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"stoa\",\"reportingPortfolio\":\"NPJ\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"47bc03d0-3585-4ffa-8cd0-2b41a345f8ed\",\"owner\":[],\"postedDate\":\"June 12th, 2024\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"published-in-journal\",\"subjectAreas\":[{\"id\":32574933,\"name\":\"Biological sciences/Drug discovery/Biomarkers/Predictive markers\"},{\"id\":32574934,\"name\":\"Biological sciences/Cancer/Cancer therapy/Targeted therapies\"}],\"tags\":[],\"updatedAt\":\"2025-01-06T10:39:20+00:00\",\"versionOfRecord\":{\"articleIdentity\":\"rs-4397695\",\"link\":\"https://doi.org/10.1038/s41698-024-00787-4\",\"journal\":{\"identity\":\"npj-precision-oncology\",\"isVorOnly\":false,\"title\":\"npj Precision Oncology\"},\"publishedOn\":\"2025-01-04 05:00:00\",\"publishedOnDateReadable\":\"January 4th, 2025\"},\"versionCreatedAt\":\"2024-06-12 04:53:06\",\"video\":\"\",\"vorDoi\":\"10.1038/s41698-024-00787-4\",\"vorDoiUrl\":\"https://doi.org/10.1038/s41698-024-00787-4\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-4397695\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-4397695\",\"identity\":\"rs-4397695\",\"version\":[\"v1\"]},\"buildId\":\"zQwnuV7TCBrMSSSToR1PI\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}