{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T12:02:43Z","timestamp":1791460963427,"version":"4.3.4"},"reference-count":52,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,7,6]],"date-time":"2025-07-06T00:00:00Z","timestamp":1751760000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Science and Technology-Philippine Council for Health Research and Development (DOST-PCHRD)"},{"name":"2022 scholarships from the Ministry of Foreign Affairs and International Cooperation the Republic of Italy (MAECI)"},{"name":"Fondazione Italiana Fegato ONLUS"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hepatocellular carcinoma (HCC) remains a major clinical challenge due to its high recurrence rate and limited response to monotherapies, such as sorafenib\u2014the standard first-line therapy for advanced HCC. This is partly attributed to its cellular heterogeneity. Increasing evidence implies SRC family kinase (SFK) activation in HCC progression, highlighting the potential of SRC-targeted therapies. In this study, we observed that SRC and YES1 were significantly upregulated in clinical HCC specimens compared to its adjacent non-tumoral tissues (p &lt; 0.001), suggesting relevance as therapeutic targets. High SRC expression was noticed in patients with poor prognosis, as confirmed in TCGA cohort. To evaluate the efficacy of dual targeting, we assessed the combination between SRC inhibitors, saracatinib and dasatinib, with sorafenib in six hepatic cell models, representing both S1 and S2 subtypes. Cytotoxicity assays demonstrated reduced cell viability with the combination therapies compared to either monotherapy, irrespective of the HCC subtype. Wound healing and Transwell migration assays revealed inhibition of cell migration and invasion following combination treatment, underscoring its potential to suppress metastatic behavior. RT-qPCR analysis further confirmed downregulation of the expression of MMP2 and MMP9, genes associated with HCC cell invasion. Additionally, combined therapies decreased VEGFA and HIF1A expression compared to sorafenib alone, suggesting a potential to counteract the adaptive resistance mechanisms of cells to sorafenib. In summary, the combination of SFK inhibitors with sorafenib significantly enhances anti-tumor activity, offering a promising strategy to address HCC cellular heterogeneity and improve treatment efficacy.<\/jats:p>","DOI":"10.3390\/ijms26136506","type":"journal-article","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T08:58:23Z","timestamp":1751878703000},"page":"6506","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Dual Inhibition of SRC Family Kinases and Sorafenib Enhances Anti-Tumor Activity in Hepatocellular Carcinoma Cells"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7931-7489","authenticated-orcid":false,"given":"Loraine Kay","family":"Cabral","sequence":"first","affiliation":[{"name":"Liver Cancer Unit, Fondazione Italiana Fegato ONLUS, AREA Science Park, Campus Basovizza, 34149 Trieste, Italy"},{"name":"Philippine Council for Health Research and Development, Department of Science and Technology, Saliksik Building, Science Community Complex General Santos Ave., Bicutan, Taguig City 1631, Philippines"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyrollah","family":"Disoma","sequence":"additional","affiliation":[{"name":"Liver Cancer Unit, Fondazione Italiana Fegato ONLUS, AREA Science Park, Campus Basovizza, 34149 Trieste, Italy"},{"name":"Doctoral School of Molecular Biomedicine, Department of Life Sciences, University of Trieste, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Tarchi","sequence":"additional","affiliation":[{"name":"General Surgery Department, Azienda Sanitaria Universitaria Giuliano Isontina, 34128 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Korri Elvanita","family":"El-Khobar","sequence":"additional","affiliation":[{"name":"Eijkman Research Center for Molecular Biology, Research Organization for Health, National Research and Innovation Agency of Indonesia (BRIN), Jakarta Pusat 10340, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agustiningsih","family":"Agustiningsih","sequence":"additional","affiliation":[{"name":"Eijkman Research Center for Molecular Biology, Research Organization for Health, National Research and Innovation Agency of Indonesia (BRIN), Jakarta Pusat 10340, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Dituri","sequence":"additional","affiliation":[{"name":"Personalized Medicine Laboratory, National Institute of Gastroenterology \u201cS. De Bellis\u201d IRCCS Research Hospital, Via Turi 27, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6596-7595","authenticated-orcid":false,"given":"Claudio","family":"Tiribelli","sequence":"additional","affiliation":[{"name":"Liver Cancer Unit, Fondazione Italiana Fegato ONLUS, AREA Science Park, Campus Basovizza, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9699-7578","authenticated-orcid":false,"given":"Caecilia","family":"Sukowati","sequence":"additional","affiliation":[{"name":"Liver Cancer Unit, Fondazione Italiana Fegato ONLUS, AREA Science Park, Campus Basovizza, 34149 Trieste, Italy"},{"name":"Eijkman Research Center for Molecular Biology, Research Organization for Health, National Research and Innovation Agency of Indonesia (BRIN), Jakarta Pusat 10340, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2334","DOI":"10.1097\/CM9.0000000000003264","article-title":"Global Epidemiology of Liver Cancer 2022: An Emphasis on Geographic Disparities","volume":"137","author":"Li","year":"2024","journal-title":"Chin. 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