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The mammalian target of rapamycin\/sirolimus (mTOR) and microtubules are prominent druggable targets for HCC. In this study, we demonstrated that co-targeting mTOR using mTOR inhibitors (everolimus and sirolimus) along with the microtubule inhibitor vinorelbine yielded results superior to those of the monotherapies in HCC PDX models. Our research showed that the vinorelbine arrests cells at the mitotic phase, induces apoptosis, and normalizes tumor blood vessels but upregulates survivin and activates the mTOR\/p70S6K\/4EBP1 pathway. The addition of the everolimus significantly improved the tumor response to the vinorelbine, leading to improved overall survival (OS) in most tested orthotopic HCC PDX models. The mechanistic investigation revealed that this marked antitumor effect was accompanied by the downregulations of mTOR targets (p-p70S6K, p-4EBP1, and p-S6K); several key cell-cycle regulators; and the antiapoptotic protein survivin. These effects did not compromise the normalization of the blood vessels observed in response to the vinorelbine in the vinorelbine-sensitive PDX models or to the everolimus in the everolimus-sensitive PDX models. The combination of the everolimus and vinorelbine (everolimus\/vinorelbine) also promoted apoptosis with minimal toxicity. Given the cost-effectiveness and established effectiveness of everolimus, and especially sirolimus, this strategy warrants further investigation in early-phase clinical trials.<\/jats:p>","DOI":"10.3390\/ijms25010017","type":"journal-article","created":{"date-parts":[[2023,12,19]],"date-time":"2023-12-19T04:18:37Z","timestamp":1702959517000},"page":"17","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Everolimus Acts in Synergy with Vinorelbine to Suppress the Growth of Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"25","author":[{"given":"Hung","family":"Huynh","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Endocrinology, National Cancer Centre Singapore, Singapore 168583, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khee Chee","family":"Soo","sequence":"additional","affiliation":[{"name":"Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore 168583, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21387","article-title":"Cancer statistics, 2017","volume":"67","author":"Siegel","year":"2017","journal-title":"CA Cancer J. 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