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dc.contributor.authorElMokh, O
dc.contributor.authorRuffieux-Daidie, D
dc.contributor.authorRoelli, MA
dc.contributor.authorStooss, A
dc.contributor.authorPhillips, WA
dc.contributor.authorGertsch, J
dc.contributor.authorDettmer, MS
dc.contributor.authorCharles, R-P
dc.date.accessioned2020-12-18T03:26:57Z
dc.date.available2020-12-18T03:26:57Z
dc.date.issued2017-04-11
dc.identifierpii: 15599
dc.identifier.citationElMokh, O., Ruffieux-Daidie, D., Roelli, M. A., Stooss, A., Phillips, W. A., Gertsch, J., Dettmer, M. S. & Charles, R. -P. (2017). Combined MEK and Pi3 '-kinase inhibition reveals synergy in targeting thyroid cancer in vitro and in vivo. ONCOTARGET, 8 (15), pp.24604-24620. https://doi.org/10.18632/oncotarget.15599.
dc.identifier.issn1949-2553
dc.identifier.urihttp://hdl.handle.net/11343/255774
dc.description.abstractAnaplastic thyroid cancers and radioiodine resistant thyroid cancer are posing a major treat since surgery combined with Iodine131 therapy is ineffective on them. Small-molecule inhibitors are presenting a new hope for patients, but often lead to drug resistance in many cancers. Based on the major mutations found in thyroid cancer, we propose the combination of a MEK inhibitor and a Pi3'-kinase inhibitor in pre-clinical models. We used human thyroid cancer cell lines and genetically engineered double mutant BRAFV600E PIK3CAH1047R mice to evaluate the effect of both inhibitors separately or in combination in terms of proliferation and signaling in vitro; tumor burden, histology, cell death induction and tumor markers expression in vivo. The combination of MEK and Pi'3-kinase inhibition shows a synergistic effect in term of proliferation and apoptosis induction through Survivin down-regulation in vitro. We show for the first time the effects of the combination of a MEK inhibitor and Pi3'-kinase inhibitor in a genetically engineered mouse model of aggressively lethal thyroid cancer. In fine, the two drugs cooperate to promote tumor shrinkage by inducing a proliferation arrest and an elevation of apoptosis in vivo. Moreover, a phenotypic reversion is also observed with a partial restoration of normal thyroid marker transcription, and thyroid cancer marker expression reduction.In conclusion, combination therapy of MEK and Pi3'-kinase inhibition synergizes to target double mutant thyroid cancer in vitro and in vivo. This multidrug approach could readily be translated into clinical practice and bring new perspectives for the treatment of incurable thyroid carcinoma.
dc.languageEnglish
dc.publisherIMPACT JOURNALS LLC
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleCombined MEK and Pi3 '-kinase inhibition reveals synergy in targeting thyroid cancer in vitro and in vivo
dc.typeJournal Article
dc.identifier.doi10.18632/oncotarget.15599
melbourne.affiliation.departmentSir Peter MacCallum Department of Oncology
melbourne.source.titleOncotarget
melbourne.source.volume8
melbourne.source.issue15
melbourne.source.pages24604-24620
melbourne.identifier.nhmrc1080491
dc.rights.licenseCC BY
melbourne.elementsid1207279
melbourne.contributor.authorPhillips, Wayne
dc.identifier.eissn1949-2553
melbourne.identifier.fundernameidNHMRC, 1080491
melbourne.accessrightsOpen Access


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