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- W4361818054 abstract "<div>Abstract<p><b>Purpose:</b> Sixty percent of papillary thyroid cancers (PTC) have an oncogenic (V600E) BRAF mutation. Inhibitors of BRAF and its substrates MEK1/2 are showing clinical promise in <i>BRAF<sup>V600E</sup></i> PTC. PTC progression can be decades long, which is challenging in terms of toxicity and cost. We previously found that MEK1/2 require copper (Cu) for kinase activity and can be inhibited with the well-tolerated and economical Cu chelator tetrathiomolybdate (TM). We therefore tested TM for antineoplastic activity in <i>BRAF<sup>V600E</sup></i>-positive PTC.</p><p><b>Experimental Design:</b> The efficacy of TM alone and in combination with current standard-of-care lenvatinib and sorafenib or BRAF and MEK1/2 inhibitors vemurafenib and trametinib was examined in <i>BRAF<sup>V600</sup></i><sup>E</sup>-positive human PTC cell lines and a genetically engineered mouse PTC model.</p><p><b>Results:</b> TM inhibited MEK1/2 kinase activity and transformed growth of PTC cells. TM was as or more potent than lenvatinib and sorafenib and enhanced the antineoplastic activity of sorafenib and vemurafenib. Activated ERK2, a substrate of MEK1/2, overcame this effect, consistent with TM deriving its antineoplastic activity by inhibiting MEK1/2. Oral TM reduced tumor burden and vemurafenib in a <i>Braf<sup>V600E</sup></i>-positive mouse model of PTC. This effect was ascribed to a reduction of Cu in the tumors. TM reduced P-Erk1/2 in mouse PTC tumors, whereas genetic reduction of Cu in developing tumors trended towards a survival advantage. Finally, TM as a maintenance therapy after cessation of vemurafenib reduced tumor volume in the aforementioned PTC mouse model.</p><p><b>Conclusions:</b> TM inhibits <i>BRAF<sup>V600E</sup></i>-driven PTC through inhibition of MEK1/2, supporting clinical evaluation of chronic TM therapy for this disease. <i>Clin Cancer Res; 24(17); 4271–81. ©2018 AACR</i>.</p></div>" @default.
- W4361818054 created "2023-04-05" @default.
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- W4361818054 date "2023-03-31" @default.
- W4361818054 modified "2023-09-27" @default.
- W4361818054 title "Data from Copper Chelation as Targeted Therapy in a Mouse Model of Oncogenic BRAF-Driven Papillary Thyroid Cancer" @default.
- W4361818054 doi "https://doi.org/10.1158/1078-0432.c.6527415" @default.
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