RANK pathway inhibition sensitizes triple-negative breast cancer to CDK4/6 inhibitors and enhances immune response

RANK pathway inhibition sensitizes triple-negative breast cancer to CDK4/6 inhibitors and enhances immune response | 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 RANK pathway inhibition sensitizes triple-negative breast cancer to CDK4/6 inhibitors and enhances immune response Sandra Casimiro, Inês Gomes, Maria Martelo, Rúben Vilela, Sofia Torres, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5377453/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 29 May, 2025 Read the published version in Molecular Cancer Therapeutics → Version 1 posted You are reading this latest preprint version Abstract Despite chemotherapy's limitations and toxic effects, it remains the primary treatment for most triple-negative breast cancer (TNBC) patients. While cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy have revolutionized luminal breast cancer treatment, CDK4/6i alone are largely ineffective in TNBC, even with functional retinoblastoma protein (pRB). The receptor activator of nuclear factor-κB (RANK) pathway has been linked to poor prognosis in TNBC. Previous research connected RANK with resistance to CDK4/6i in luminal breast cancer, which could be reversed by RANK ligand inhibitors (RANKLi). In this study, RANK knockdown or RANKLi treatment sensitized pRB-proficient TNBC cells to CDK4/6i, reducing tumor growth and metastasis. Combining CDK4/6i with RANKLi enhanced cell cycle arrest and elicited an immune response in the tumor microenvironment across BC subtypes. These findings suggest that combining CDK4/6i and RANKLi is a promising therapeutic approach for pRB-proficient TNBC, with potential immunomodulatory benefits, warranting further investigation. Biological sciences/Cancer/Breast cancer Biological sciences/Cancer/Cancer therapy/Targeted therapies Full Text Additional Declarations Yes there is potential Competing Interest. S.C. and L.C. received research support from Amgen Inc. in the form of supplies. A.M., C.A., R.S. and L.C. have received honoraria as consultants/speakers and/or travel/logistics support from Amgen, Novartis, and Pfizer. Supplementary Files SupplementaryTable2Gomesetal.xlsx SupplementaryinformationGomesetal.pdf Cite Share Download PDF Status: Published Journal Publication published 29 May, 2025 Read the published version in Molecular Cancer Therapeutics → 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. 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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-5377453","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":378724983,"identity":"f63ba11b-d51d-4148-901d-2dff56979269","order_by":0,"name":"Sandra Casimiro","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8ElEQVRIiWNgGAWjYJACCQjF2MCQwMAgx8BMqhZjqBYDYrRAQGIDAwEt8u1nD96uqGGQ5+8/3Lrh4R6b9Pnu3KkbGHf8wanF4ExesuWZYwyGM24ktt1IeJaWu/Ew77YbjGdw22LAkGMm2cAG9MUNRqCWA4dzNzaDtLThcVj/G6CWfwwJ8ucPgrWkGxLSwnADaEtjG0OCwYFEsJYEeWYCWgxuvDG2bOyTMNwI9suBNMMNIC2JZ4zxOCzH8GbDNxt5ufPHn938ccBGXr7/7LYbH3fI4XYYBCBFjcEBBkTsEAfkQaoZSdIyCkbBKBgFwxwAAE5MW44LNWboAAAAAElFTkSuQmCC","orcid":"","institution":"Fundação GIMM - 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