{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T23:52:36Z","timestamp":1789689156064,"version":"4.0.1"},"reference-count":75,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:00:00Z","timestamp":1759968000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Singapore Ministry of Health\u2019s National Medical Research Council","award":["NMRC\/MOHIAFCAT2\/006\/2016"],"award-info":[{"award-number":["NMRC\/MOHIAFCAT2\/006\/2016"]}]},{"name":"National University Hospital of Singapore Central Grant","award":["CG21APR1005"],"award-info":[{"award-number":["CG21APR1005"]}]},{"name":"National University Hospital of Singapore Central Grant","award":["CGAug16M005"],"award-info":[{"award-number":["CGAug16M005"]}]},{"DOI":"10.13039\/501100001381","name":"National Research Foundation of Singapore under its Competitive Research Program","doi-asserted-by":"publisher","award":["NRF-CRP17-2017-05"],"award-info":[{"award-number":["NRF-CRP17-2017-05"]}],"id":[{"id":"10.13039\/501100001381","id-type":"DOI","asserted-by":"publisher"}]},{"name":"SingHealth DUKE-NUS Academic Medicine Research Grant","award":["AM\/TP049\/2021"],"award-info":[{"award-number":["AM\/TP049\/2021"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hepatocellular carcinoma (HCC) is a deadly liver cancer characterized by dysregulated signaling and aberrant cell-cycle control. The FGFR4\/FGF19 pathway is dysregulated in HCC and other cancers. Inhibitors targeting the FGF19\/FGFR4 pathway, including the FGF19\/FGFR4 inhibitor FGF401, have been investigated in HCC and other cancers; however, nearly all patients who initially respond eventually develop resistance shortly after starting therapy, highlighting the urgent need for new treatment strategies to overcome drug resistance. In the present study, we report that chronic treatment of the FGF19\/FGFR4-expressing HCC25\u22120705A line with FGF401 led to acquired resistance. FGF401-resistant tumors exhibited upregulation of FGFRs and activation of the PI3K\/AKT\/mTOR\/p70S6K pathway. Combination therapy with FGF401 and the mammalian target of rapamycin (mTOR) inhibitor everolimus (FGF401\/everolimus) resulted in more complete tumor growth inhibition, delayed the onset of resistance, and prolonged overall survival (OS) in mice bearing orthotopic HCC tumors. The FGF401\/everolimus combination effectively suppressed tumor cell proliferation; promoted apoptosis; reduced tumor hypoxia via blood vessel normalization; and downregulated key proteins involved in proliferation, survival, metastasis, and angiogenesis. These preclinical findings provide a strong rationale for clinical trials combining FGFR4 and mTOR inhibitors in HCC patients with FGF19\/FGFR4\/mTOR-dependent tumors.<\/jats:p>","DOI":"10.3390\/ijms26199818","type":"journal-article","created":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:50:16Z","timestamp":1760107816000},"page":"9818","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Reactivation of the PI3K\/mTOR Signaling Pathway Confers Resistance to the FGFR4 Inhibitor FGF401"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7847-3981","authenticated-orcid":false,"given":"Hung","family":"Huynh","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Endocrinology, National Cancer Centre Singapore, Singapore 168583, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0069-1599","authenticated-orcid":false,"given":"Wai Har","family":"Ng","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Endocrinology, National Cancer Centre Singapore, Singapore 168583, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1016\/j.jhep.2022.08.021","article-title":"Global burden of primary liver cancer in 2020 and predictions to 2040","volume":"77","author":"Rumgay","year":"2022","journal-title":"J Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4536","DOI":"10.3748\/wjg.v24.i40.4536","article-title":"Dimensions of hepatocellular carcinoma phenotypic diversity","volume":"24","author":"Nieto","year":"2018","journal-title":"World J. 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