Format

Send to

Choose Destination

See 1 citation found by title matching your search:

Oncotarget. 2017 Feb 21;8(8):12576-12595. doi: 10.18632/oncotarget.14990.

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

Author information

1
Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC, USA.
2
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
3
Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University Medical Center, Washington, DC, USA.
4
MedStar Franklin Square Medical Center, Baltimore, MD, USA.
5
Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA.

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.

KEYWORDS:

BRAF; ERK pathway; drug repurposing; mebendazole; melanoma

PMID:
28157711
PMCID:
PMC5355037
DOI:
10.18632/oncotarget.14990
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Impact Journals, LLC Icon for PubMed Central
Loading ...
Support Center