KIF18A Inhibition as a Therapeutic Strategy in Cancers with Rb Pathway Inactivation

KIF18A Inhibition as a Therapeutic Strategy in Cancers with Rb Pathway Inactivation | 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 KIF18A Inhibition as a Therapeutic Strategy in Cancers with Rb Pathway Inactivation Samuel Bakhoum, Timothy Bowler, Celia Andreu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9441895/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 Chromosomal instability is a hallmark of human cancer and it is associated with poor outcomes and therapeutic resistance. KIF18A inhibition has emerged as a therapeutic strategy for chromosomally unstable cancers, but clinical development has been limited by the absence of a predictive response biomarker. Here we identify strong, diffuse p16INK4a expression, a well-established surrogate marker of Rb-pathway inactivation, as a candidate predictive biomarker of response to KIF18A inhibition, and show that Rb-pathway inactivation marks a biologically distinct subset of cancers sensitive to this therapeutic approach. In sensitive models, low Rb activity is associated with robust spindle assembly checkpoint signaling and prolonged mitotic arrest following KIF18A inhibition. Weakening the spindle assembly checkpoint in this context is sufficient to confer resistance. Across three independent pan-cancer sensitivity datasets, Rb-pathway altered models were significantly more sensitive than histology-matched Rb-intact comparators. Guided by this mechanism, we retrospectively analyzed p16INK4a expression by immunohistochemistry (IHC) in pre-treatment tumor biopsies from 79 heavily pre-treated high-grade serous ovarian cancer patients across three dose-escalation or expansion cohorts and treated with two different KIF18A inhibitors (sovilnesib and VLS-1488) sharing a common mechanism of action. p16INK4a-high tumors showed substantially higher objective response rates than their p16INK4a-low counterparts (36.0% versus 2.2%; P = 0.0002) and markedly longer progression-free survival (median 24.3 versus 7.9 weeks; hazard ratio, 0.16; P < 0.0001). These findings establish p16INK4a as a mechanistically-based, clinically implementable biomarker of clinical response to KIF18A inhibition that is poised to support pan-cancer development of KIF18A inhibitors guided by Rb-pathway inactivation. Oncology Chromosomal instability KIF18A sovilnesib VLS-1488 p16INK4a p16 Rb Cyclin E CDKN2A Full Text Additional Declarations The authors declare potential competing interests as follows: C.A., A.A., S.C., A.R., S.B., N.B., D.P.S., T.B. and S.F.B. are employees of Volastra Therapeutics, from which they receive compensation and in which they hold equity. D.P.S. and S.F.B. serve as directors of Volastra Therapeutics. S.F.B., T.B., D.P.S., S.C. and S.B. are inventors on patent appli-cations related to p16, RB-pathway inactivation, and KIF18A sensitivity in cancer. 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. 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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-9441895","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":624538752,"identity":"f7fbc11c-2fe4-4297-8169-ce76b6ac3063","order_by":0,"name":"Samuel Bakhoum","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA90lEQVRIiWNgGAWjYNCCAoYEBh4eEMsGiBkbDxDWYgDXkgbS0kCSlsNgPl4t8u2n0yQ+GDDk8fecPfiYN+e83dr2w0BbamyicZp/Jneb5AwDhmKJs33JxrzbbidvO5MI1HIsLbcBp5Nyt0nzGDAkNpznMZMGaTE7ANTC2HAYpxb5/rfbpP8AtcyHaDmXbHb+IX4tDDeAtgDtStxwtgek5YCd2Q0CthjceLvZssdAotjwzBljw7nbkhPMbgBtScDjF/n+3I03flTY5MmdyTF88Habnb3Z+fSHDz7U2OB2GARIwFmJYJUJ+JWjAntSFI+CUTAKRsHIAABUaGHWeWnnmwAAAABJRU5ErkJggg==","orcid":"","institution":"Volastra Therapeutics Inc. and Geisel School of Medicine at Dartmouth","correspondingAuthor":true,"prefix":"","firstName":"Samuel","middleName":"","lastName":"Bakhoum","suffix":""},{"id":624538786,"identity":"a32e62f6-701a-44dd-86fd-7d6900b7e72e","order_by":1,"name":"Timothy Bowler","email":"","orcid":"","institution":"Volastra Therapeutics Inc.","correspondingAuthor":false,"prefix":"","firstName":"Timothy","middleName":"","lastName":"Bowler","suffix":""},{"id":624538787,"identity":"a9711db4-0341-41db-9b33-ccbe8a7ccba5","order_by":2,"name":"Celia Andreu","email":"","orcid":"","institution":"Volastra Therapeutics Inc.","correspondingAuthor":false,"prefix":"","firstName":"Celia","middleName":"","lastName":"Andreu","suffix":""}],"badges":[],"createdAt":"2026-04-16 20:27:26","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":true,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":true,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-9441895/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9441895/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107483694,"identity":"520ab1d6-d476-44ea-bed6-5363c5f64457","added_by":"auto","created_at":"2026-04-22 02:28:52","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2315833,"visible":true,"origin":"","legend":"","description":"","filename":"Rbp16KIF18Asensitivity.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9441895/v1_covered_625aca6b-418f-4222-a87d-8ae35c0e4dcf.pdf"}],"financialInterests":"The authors declare potential competing interests as follows: C.A., A.A., S.C., A.R., S.B., N.B., D.P.S., T.B. and S.F.B. are employees of Volastra Therapeutics, from which they receive compensation and in which they hold equity. 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KIF18A inhibition has emerged as a therapeutic strategy for chromosomally unstable cancers, but clinical development has been limited by the absence of a predictive response biomarker. Here we identify strong, diffuse p16INK4a expression, a well-established surrogate marker of Rb-pathway inactivation, as a candidate predictive biomarker of response to KIF18A inhibition, and show that Rb-pathway inactivation marks a biologically distinct subset of cancers sensitive to this therapeutic approach. In sensitive models, low Rb activity is associated with robust spindle assembly checkpoint signaling and prolonged mitotic arrest following KIF18A inhibition. Weakening the spindle assembly checkpoint in this context is sufficient to confer resistance. Across three independent pan-cancer sensitivity datasets, Rb-pathway altered models were significantly more sensitive than histology-matched Rb-intact comparators. 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