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Ovid MEDLINE(R)
28157711
The repurposed anthelmintic mebendazole in combination with trametinib suppresses refractory NRASQ61K melanoma.
Oncotarget. 8(8):12576-12595, 2017 Feb 21
Oncotarget. 8(8):12576-12595, 2017 Feb 21
Oncotarget
2017
FY2017
2017-05-06
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.
English
*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 Assays
MedStar Franklin Square Medical Center
Journal Article
Abdussamad, Maryam
Zapas, John
Zhou, Hengbo
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 H
https://dx.doi.org/10.18632/oncotarget.14990
https://dx.doi.org/10.18632/oncotarget.14990
ART
Article
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Article
authcat
authcat
2017-05-06
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28157711
28157711
2017-05-06
2017-05-06
ART
2702
2702