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Histopathological and biochemical studies of CCA show frequent dysregulation of the phosphatidylinositol 3\u2010kinase\/AKT\/mammalian target of rapamycin (mTOR) pathway. Therefore, we investigated the efficacy of the mTOR inhibitor RAD001 and the impact of AKT signaling following mTOR inhibition in the treatment of CCA. RAD001 significantly inhibits proliferation of CCA cell lines, however, a concentration\u2010dependent and isoform specific feedback activation of the three AKT isoforms (AKT1, AKT2 and AKT3) was observed after mTOR inhibition. As activation of AKT might limit the RAD001\u2010mediated anti\u2010tumor effect, the efficacy of combined mTOR and AKT inhibition was investigated using the allosteric AKT inhibitor MK\u20102206. Our results show that inhibition of AKT potentiates the efficacy of mTOR inhibition both <jats:italic>in vitro<\/jats:italic> and in a xenograft mouse model <jats:italic>in vivo<\/jats:italic>. Mechanistically, the antiproliferative effect of the pan\u2010AKT inhibitor MK2206 in the CCA cell line TFK\u20101 was due to inhibition of AKT1 and AKT2, because knockdown of either AKT1 or AKT2, but not AKT3, showed a synergistic reduction of cell proliferation in combination with mTOR treatment. Finally, using an AKT isoform specific <jats:italic>in vitro<\/jats:italic> kinase assay, enzymatic activity of each of the three AKT isoforms was detected in all tissue samples from CCA patients, analyzed. In summary, our preclinical data suggest that combined targeting of mTOR and AKT using RAD001 and MK\u20102206 might be a new, effective strategy for the treatment of CCA.<\/jats:p>","DOI":"10.1002\/ijc.28214","type":"journal-article","created":{"date-parts":[[2013,4,16]],"date-time":"2013-04-16T09:32:42Z","timestamp":1366104762000},"page":"2065-2076","source":"Crossref","is-referenced-by-count":71,"title":["Combined targeting of AKT and mTOR using MK\u20102206 and RAD001 is synergistic in the treatment of cholangiocarcinoma"],"prefix":"10.1002","volume":"133","author":[{"given":"Florian","family":"Ewald","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary and Transplant Surgery University Medical Center Hamburg\u2010Eppendorf Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Grabinski","sequence":"additional","affiliation":[{"name":"Center for Experimental Medicine Institute of Biochemistry and Signal Transduction, 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