Systematic decoding of the resistance mechanisms and therapeutic vulnerabilities in TKI-resistant hepatocellular carcinoma

Systematic decoding of the resistance mechanisms and therapeutic vulnerabilities in TKI-resistant hepatocellular carcinoma | 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 Systematic decoding of the resistance mechanisms and therapeutic vulnerabilities in TKI-resistant hepatocellular carcinoma Teng Fei, Shixin Ma, You Li, Xiaofeng Wang, Xiaolong Cheng, Zihan Li, and 21 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8651907/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 Drug resistance to multiple tyrosine kinase inhibitors (TKIs) is a major issue during clinical management of hepatocellular carcinoma (HCC). Here, through multiplexed in vitro and in vivo CRISPR knockout and base editing screens, we elucidate the resistance mechanisms of HCC to typical TKIs (sorafenib, lenvatinib and regorafenib). Multiple genetic or epigenetic alterations can drive resistance to these TKIs through divergent mechanisms. Among them, a tumor cell-intrinsic (rather than tumor microenvironment-driven) extracellular matrix remodeling mechanism stands out across multiple resistance models and clinical samples. Using druggable gene CRISPR knockout screens, we identify proteasome as a prominent and convergent vulnerability of multiple TKI-resistant HCC cells. We further validate the efficacy of clinically available proteasome inhibitor bortezomib in treating TKI-resistant HCC in multiple preclinical models. Mechanistically, increased p21 expression and dysregulated proteolytic machineries in TKI-resistant tumors account for the pronounced sensitivity to bortezomib. Our work not only delineates a comprehensive landscape of drug resistance mechanisms in TKI-treated HCC, but also suggests actionable therapeutics with immediate clinical potential against these tumors. Biological sciences/Cancer Biological sciences/Genetics/Functional genomics Health sciences/Diseases/Cancer CRISPR screen tyrosine kinase inhibitor resistance hepatocellular carcinoma liver cancer sorafenib lenvatinib regorafenib Full Text Additional Declarations Yes there is potential Competing Interest. A patent application is being filed through Northeastern University with T.F. and S.M. as co-inventors regarding applying proteasome inhibitors to treat TKI-resistant HCC. Supplementary Files SupplementaryTable1.Clinicopathologiccharacteristicsofpatientsinthecohort.docx Supplementary Table 1. Clinicopathologic characteristics of patients in the cohort. SupplementaryData1.InvitroCRISPRscreendata.xlsx Supplementary Data 1 SupplementaryData2.InvivoCRISPRscreendata.xlsx Supplementary Data 2 SupplementaryData3.Baseeditingscreendata.xlsx Supplementary Data 3 SupplementaryData4.RNAseqandproteomicsdata.xlsx Supplementary Data 4 SupplementaryData5.DruggablegeneCRISPRscreendata.xlsx Supplementary Data 5 SupplementaryData6.Oligosandprimers.xlsx Supplementary Data 6 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-8651907","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":578156287,"identity":"a949e0d1-2c24-4667-a1d2-78fa1ad8f07e","order_by":0,"name":"Teng 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