The repurposed anthelmintic mebendazole in combination with trametinib suppresses refractory NRASQ61K melanoma.

MedStar author(s):
Citation: Oncotarget. 8(8):12576-12595, 2017 Feb 21PMID: 28157711Institution: MedStar Franklin Square Medical CenterForm of publication: Journal ArticleMedline article type(s): Journal ArticleSubject headings: *Antineoplastic Combined Chemotherapy Protocols/pd [Pharmacology] | *Cell Proliferation/de [Drug Effects] | *Mebendazole/pd [Pharmacology] | *Melanoma/pa [Pathology] | *Pyridones/pd [Pharmacology] | *Pyrimidinones/pd [Pharmacology] | Animals | Antinematodal Agents/pd [Pharmacology] | Cell Line, Tumor | GTP Phosphohydrolases | Humans | Immunoblotting | Melanoma/ge [Genetics] | Membrane Proteins | Mice | Protein Array Analysis | Xenograft Model Antitumor AssaysYear: 2017ISSN:
  • 1949-2553
Name of journal: OncotargetAbstract: 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.All authors: Abdussamad M, Atkins MB, Byers SW, Calvert V, Chen YS, Dakshanamurthy S, Fang HB, Gaur A, Petricoin EF, Rosenthal DS, Simbulan-Rosenthal CM, Zapas J, Zhou HFiscal year: FY2017Digital Object Identifier: Date added to catalog: 2017-05-06
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Journal Article MedStar Authors Catalog Article 28157711 Available 28157711

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.

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