Oncotarget

Priority Research Papers:

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

Cynthia M. Simbulan-Rosenthal, Sivanesan Dakshanamurthy, Anirudh Gaur, You-Shin Chen, Hong-Bin Fang, Maryam Abdussamad, Hengbo Zhou, John Zapas, Valerie Calvert, Emanuel F. Petricoin, Michael B. Atkins, Stephen W. Byers and Dean S. Rosenthal _

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2017; 8:12576-12595. https://doi.org/10.18632/oncotarget.14990

Metrics: PDF 2415 views  |   HTML 5259 views  |   ?  


Abstract

Cynthia M. Simbulan-Rosenthal1,*, Sivanesan Dakshanamurthy1,2,*, Anirudh Gaur1, You-Shin Chen1, Hong-Bin Fang3, Maryam Abdussamad4, Hengbo Zhou4, John Zapas4, Valerie Calvert5, Emanuel F. Petricoin5, Michael B. Atkins2, Stephen W. Byers1,2 and Dean S. Rosenthal1

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

* These authors are co-first authors

Correspondence to:

Dean S. Rosenthal, email:

Keywords: mebendazole, drug repurposing, melanoma, ERK pathway, BRAF

Received: March 31, 2016 Accepted: October 13, 2016 Published: February 02, 2017

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 14990