August 18, 2016 Liz Amdahl

Cutaneous wound healing through paradoxical MAPK activation by BRAF inhibitors

Helena Escuin-Ordinas, Shuoran Li, Michael W. Xie, Lu Sun, Willy Hugo, Rong Rong Huang, Jiang Jiao, Felipe Meira de-Faria, Susan Realegeno, Paige Krystofinski, Ariel Azhdam, Sara Marie D. Komenan, Mohammad Atefi, Begona Comin-Aunduix, Matteo Pellegrini, Alistar J Cochran, Robert Modlin, Harvey R Herschman, Roger S. Lo, William H. McBride, Tatiana Segura and Antoni Ribas

Nature Communications | Published August 1st, 2016 | DOI: 10.1038/ncomms12348

BRAF inhibitors are highly effective therapies for the treatment of BRAFV600-mutated melanoma, with the main toxicity being a variety of hyperproliferative skin conditions due to paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in BRAF wild-type cells. Most of these hyperproliferative skin changes improve when a MEK inhibitor is co-administered, as it blocks paradoxical MAPK activation. Here we show how the BRAF inhibitor vemurafenib accelerates skin wound healing by inducing the proliferation and migration of human keratinocytes through extracellular signal-regulated kinase (ERK) phos-phorylation and cell cycle progression. Topical treatment with vemurafenib in two wound-healing mice models accelerates cutaneous wound healing through paradoxical MAPK activation; addition of a mitogen-activated protein kinase kinase (MEK) inhibitor reverses the benefit of vemurafenib-accelerated wound healing. The same dosing regimen of topical BRAF inhibitor does not increase the incidence of cutaneous squamous cell carcinomas in mice. Therefore, topical BRAF inhibitors may have clinical applications in accelerating the healing of skin wounds.

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