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MEK inhibitors and their potential in the treatment of advanced melanoma: the advantages of combination therapy

Authors Tran K, Cheng M, Mitra A, Ogawa H, Shi V, Olney L, Kloxin A, Maverakis E

Received 1 August 2015

Accepted for publication 8 October 2015

Published 21 December 2015 Volume 2016:10 Pages 43—52

DOI https://doi.org/10.2147/DDDT.S93545

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Rekha Dhanwani

Peer reviewer comments 3

Editor who approved publication: Prof. Dr. Wei Duan


Khiem A Tran,1,* Michelle Y Cheng,1,* Anupam Mitra,1 Hiromi Ogawa,1 Vivian Y Shi,1 Laura P Olney,1 April M Kloxin,Emanual Maverakis1

1Department of Dermatology, University of California, Davis, Sacramento, CA, USA; 2Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE, USA

*These authors contributed equally to this work

Abstract: The treatment of melanoma has improved markedly over the last several years with the advent of more targeted therapies. Unfortunately, complex compensation mechanisms, such as those of the mitogen-activated protein kinase (MAPK) pathway, have limited the clinical benefit of these treatments. Recently, a better understanding of melanoma resistance mechanisms has given way to intelligently designed multidrug regimes. Herein, we review the extensive pathways of BRAF inhibitor (vemurafenib and dabrafenib) resistance. We also review the advantages of dual therapy, including the addition of an MEK inhibitor (cobimetinib or trametinib), which has proven to increase progression-free survival when compared to BRAF inhibitor monotherapy. Finally, this review touches on future treatment strategies that are being developed for advanced melanoma, including the possibility of triple therapy with immune checkpoint inhibitors and the work on optimizing sequential therapy.

Keywords: cobimetinib, trametinib, vemurafenib, dabrafenib, BRAF inhibitor, MAPK pathway

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