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However, mRCC often acquires resistance to sunitinib, rendering it difficult to treat with this agent. Recently, Rapalink\u20101, a drug that links rapamycin and the mTOR kinase inhibitor MLN0128, has been developed with excellent therapeutic effects against breast cancer cells carrying mTOR resistance mutations. The aim of the present study was to evaluate the in vitro and in vivo therapeutic efficacy of Rapalink\u20101 against renal cell carcinoma (RCC) compared to temsirolimus, which is commonly used as a small molecule inhibitor of mTOR and is a derivative of rapamycin. In comparison with temsirolimus, Rapalink\u20101 showed significantly greater effects against proliferation, migration, invasion and cFolony formation in sunitinib\u2010na\u00efve RCC cells. Inhibition was achieved through suppression of the phosphorylation of substrates in the mTOR signal pathway, such as p70S6K, eukaryotic translation initiation factor 4E\u2010binding protein 1 (4EBP1) and AKT. In addition, Rapalink\u20101 had greater tumor suppressive effects than temsirolimus against the sunitinib\u2010resistant 786\u2010o cell line (SU\u2010R 786\u2010o), which we had previously established, as well as 3 additional SU\u2010R cell lines established here. RNA sequencing showed that Rapalink\u20101 suppressed not only the mTOR signaling pathway but also a part of the MAPK signaling pathway, the ErbB signaling pathway and ABC transporters that were associated with resistance to several drugs. Our study suggests the possibility of a new treatment option for patients with RCC that is either sunitinib\u2010sensitive or sunitinib\u2010resistant.<\/jats:p>","DOI":"10.1111\/cas.14395","type":"journal-article","created":{"date-parts":[[2020,3,31]],"date-time":"2020-03-31T01:54:31Z","timestamp":1585619671000},"page":"1607-1618","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Potential new therapy of Rapalink\u20101, a new generation mammalian target of rapamycin inhibitor, against sunitinib\u2010resistant renal cell carcinoma"],"prefix":"10.1111","volume":"111","author":[{"given":"Kazuki","family":"Kuroshima","sequence":"first","affiliation":[{"name":"Department of Urology Graduate School of Medical and Dental Sciences Kagoshima University Kagoshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirofumi","family":"Yoshino","sequence":"additional","affiliation":[{"name":"Department of 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