SIK2 drives cisplatin chemoresistance in BRAF-wild-type anaplastic thyroid cacner by phosphorylating AURKB to activate RAD51- dependent homologous recombination

SIK2 drives cisplatin chemoresistance in BRAF-wild-type anaplastic thyroid cacner by phosphorylating AURKB to activate RAD51- dependent homologous recombination | 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 Research Article SIK2 drives cisplatin chemoresistance in BRAF-wild-type anaplastic thyroid cacner by phosphorylating AURKB to activate RAD51- dependent homologous recombination Zicheng Sun, Mingwei Liang, Xin Liu, Hongquan Zhu, Jiaqi Zhang, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9364108/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Anaplastic thyroid cancer (ATC) is an aggressive malignancy with limited therapeutic options, particularly in BRAF wild-type disease. Here, we identify salt-inducible kinase 2 (SIK2) as a key oncogenic driver that promotes ATC progression and cisplatin resistance. Mechanistically, SIK2 directly phosphorylates AURKB at Thr73, conferring a non-canonical function in DNA damage regulation. This phosphorylation enhances UCHL3-dependent stabilization of RAD51, thereby promoting homologous recombination repair and reducing cisplatin-induced DNA damage. Pharmacological inhibition of SIK2 with ARN-3236 disrupts this signaling axis, markedly sensitizes ATC to cisplatin both in vitro and in vivo. Collectively, our findings uncover a SIK2–AURKB–RAD51 signaling pathway that drives DNA repair–mediated chemoresistance and highlight SIK2 as a promising therapeutic target in BRAF wild-type ATC. Anaplastic thyroid cancer SIK2 DNA damage repair Homologous recombination Cisplatin resistance Full Text Additional Declarations No competing interests reported. Supplementary Files SIK2AURKBRAD51suppFigure.docx SIK2AURKBRAD51wb202642.pdf Cite Share Download PDF Status: Posted 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-9364108","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":626899578,"identity":"be114c41-dc74-48a8-8394-f612c0d5ae05","order_by":0,"name":"Zicheng Sun","email":"","orcid":"","institution":"Cancer Hospital of Shantou University Medical College","correspondingAuthor":false,"prefix":"","firstName":"Zicheng","middleName":"","lastName":"Sun","suffix":""},{"id":626899579,"identity":"7ef07ec5-cd9d-4263-9f80-f8b7c58c6120","order_by":1,"name":"Mingwei Liang","email":"","orcid":"","institution":"First Affiliated Hospital of Sun Yat-sen 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