{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T03:16:23Z","timestamp":1788837383931,"version":"build-2803163510"},"reference-count":36,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2014,12,2]],"date-time":"2014-12-02T00:00:00Z","timestamp":1417478400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Novartis Pharma AG"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2015,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Sequential application of target drugs is standard procedure after renal cell carcinoma (<jats:styled-content style=\"fixed-case\">RCC<\/jats:styled-content>) patients develop resistance. To optimize the sequence, antitumour effects of the <jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content> inhibitor <jats:styled-content style=\"fixed-case\">RAD<\/jats:styled-content>001 or the tyrosine kinase inhibitor (<jats:styled-content style=\"fixed-case\">TKI<\/jats:styled-content>) sorafenib on <jats:styled-content style=\"fixed-case\">RCC<\/jats:styled-content> cells with acquired resistance to the <jats:styled-content style=\"fixed-case\">TKI<\/jats:styled-content> sunitinib was evaluated. <jats:styled-content style=\"fixed-case\">RCC<\/jats:styled-content> cells were exposed to 1\u00a0\u03bcM sunitinib for 24\u00a0hrs (as control) and for 8\u00a0weeks (to induce resistance) and then switched to <jats:styled-content style=\"fixed-case\">RAD<\/jats:styled-content>001 (5\u00a0nM) or sorafenib (5\u00a0\u03bcM) for a further 8\u00a0weeks. Tumour cell growth, cell cycle progression, cell cycle regulating proteins and intracellular signalling were then investigated. Short\u2010term application of sunitinib (24\u00a0hrs) induced cell growth blockade with accumulation in the G2\/M phase. <jats:styled-content style=\"fixed-case\">RCC<\/jats:styled-content> cells became resistant to sunitinib after 8\u00a0weeks, demonstrated by accelerated cell growth along with enhanced cdk1, cdk2, loss of p27, activation of Akt, Rictor and Raptor. Switching to sorafenib only slightly reduced growth of the sunitinib resistant <jats:styled-content style=\"fixed-case\">RCC<\/jats:styled-content> cells and molecular analysis indicated distinct cross\u2010resistance. In contrast, full response was achieved when the cancer cells were treated with <jats:styled-content style=\"fixed-case\">RAD<\/jats:styled-content>001. p19 and p27 strongly increased, phosphorylated Akt, Rictor and Raptor decreased and the tumour cells accumulated in G0\/G1. It is concluded that an <jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content>\u2010inhibitor for second\u2010line therapy could be the strategy of choice after first\u2010line sunitinib failure.<\/jats:p>","DOI":"10.1111\/jcmm.12471","type":"journal-article","created":{"date-parts":[[2014,12,9]],"date-time":"2014-12-09T11:07:42Z","timestamp":1418123262000},"page":"430-441","source":"Crossref","is-referenced-by-count":25,"title":["Molecular analysis of sunitinib resistant renal cell carcinoma\u00a0cells after sequential treatment with <scp>RAD<\/scp>001\u00a0(everolimus) or sorafenib"],"prefix":"10.1111","volume":"19","author":[{"given":"Eva","family":"Juengel","sequence":"first","affiliation":[{"name":"Department of Urology Johann Wolfgang Goethe\u2010University Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Urology Johann Wolfgang 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