The repurposed anthelmintic mebendazole in combination with trametinib suppresses refractory NRASQ61K melanoma.
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.
Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC, USA.
Cynthia M
CM
Simbulan-Rosenthal
Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC, USA.|Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Sivanesan
S
Dakshanamurthy
Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC, USA.
Anirudh
A
Gaur
Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC, USA.
You-Shin
YS
Chen
Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University Medical Center, Washington, DC, USA.
Hong-Bin
HB
Fang
MedStar Franklin Square Medical Center, Baltimore, MD, USA.
Maryam
M
Abdussamad
MedStar Franklin Square Medical Center, Baltimore, MD, USA.
Hengbo
H
Zhou
MedStar Franklin Square Medical Center, Baltimore, MD, USA.
John
J
Zapas
Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA.
Valerie
V
Calvert
Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA.
Emanuel F
EF
Petricoin
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Michael B
MB
Atkins
Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC, USA.|Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Stephen W
SW
Byers
Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC, USA.
Dean S
DS
Rosenthal
D000818:Animals; D000969:Antinematodal Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D020558:GTP Phosphohydrolases; D006801:Humans; D015151:Immunoblotting; D008463:Mebendazole / Q000494:pharmacology*; D008545:Melanoma / Q000235:genetics / Q000473:pathology*; D008565:Membrane Proteins; D051379:Mice; D040081:Protein Array Analysis; D011728:Pyridones / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000969:Antinematodal Agents; D008565:Membrane Proteins; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D008463:Mebendazole; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
BRAF; ERK pathway; drug repurposing; mebendazole; melanoma