Citation: Oncotarget. 8(8):12576-12595, 2017 Feb 21.Journal: Oncotarget.Published: 2017ISSN: 1949-2553.Full author list: Simbulan-Rosenthal CM; Dakshanamurthy S; Gaur A; Chen YS; Fang HB; Abdussamad M; Zhou H; Zapas J; Calvert V; Petricoin EF; Atkins MB; Byers SW; Rosenthal DS.UI/PMID: 28157711.Subject(s): Animals | Antinematodal Agents/pd [Pharmacology] | *Antineoplastic Combined Chemotherapy Protocols/pd [Pharmacology] | Cell Line, Tumor | *Cell Proliferation/de [Drug Effects] | GTP Phosphohydrolases | Humans | Immunoblotting | *Mebendazole/pd [Pharmacology] | Melanoma/ge [Genetics] | *Melanoma/pa [Pathology] | Membrane Proteins | Mice | Protein Array Analysis | *Pyridones/pd [Pharmacology] | *Pyrimidinones/pd [Pharmacology] | Xenograft Model Antitumor AssaysInstitution(s): MedStar Franklin Square Medical CenterActivity type: Journal Article.Medline article type(s): Journal ArticleDigital Object Identifier: https://dx.doi.org/10.18632/oncotarget.14990 (Click here)Abbreviated citation: Oncotarget. 8(8):12576-12595, 2017 Feb 21.Abstract: Structure-based drug repositioning in addition to random chemical screening is now a viable route to rapid drug development. Proteochemometric computational methods coupled with kinase assays showed that mebendazole (MBZ) binds and inhibits kinases important in cancer, especially both BRAFWT and BRAFV600E. We find that MBZ synergizes with the MEK inhibitor trametinib to inhibit growth of BRAFWT-NRASQ61K melanoma cells in culture and in xenografts, and markedly decreased MEK and ERK phosphorylation. Reverse Phase Protein Array (RPPA) and immunoblot analyses show that both trametinib and MBZ inhibit the MAPK pathway, and cluster analysis revealed a protein cluster showing strong MBZ+trametinib - inhibited phosphorylation of MEK and ERK within 10 minutes, and its direct and indirect downstream targets related to stress response and translation, including ElK1 and RSKs within 30 minutes. Downstream ERK targets for cell cycle, including cMYC, were down-regulated, consistent with S- phase suppression by MBZ+trametinib, while apoptosis markers, including cleaved caspase-3, cleaved PARP and a sub-G1 population, were all increased with time. These data suggest that MBZ, a well-tolerated off-patent approved drug, should be considered as a therapeutic option in combination with trametinib, for patients with NRASQ61mut or other non-V600E BRAF mutant melanomas.