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, Jing Jiao, Felipe Meira de-Faria, Susan Realegeno, Paige Krystofinski, Ariel Azhdam, Sara Marie D. Komenan, Mohammad Atefi, Begoña Comin-Anduix, Matteo Pellegrini, Alistair J. Cochran, Robert L. Modlin, Harvey R. Herschman, Roger S. Lo, William H. McBride, Tatiana Segura and Antoni Ribas ()
Additional contact information
Helena Escuin-Ordinas: University of California, Los Angeles (UCLA)
Shuoran Li: University of California, Los Angeles (UCLA)
Michael W. Xie: University of California, Los Angeles (UCLA)
Lu Sun: University of California, Los Angeles (UCLA)
Willy Hugo: University of California, Los Angeles (UCLA)
Rong Rong Huang: University of California, Los Angeles (UCLA)
Jing Jiao: University of California, Los Angeles (UCLA)
Felipe Meira de-Faria: University of California, Los Angeles (UCLA)
Susan Realegeno: Immunology & Molecular Genetics, University of California, Los Angeles (UCLA)
Paige Krystofinski: University of California, Los Angeles (UCLA)
Ariel Azhdam: University of California, Los Angeles (UCLA)
Sara Marie D. Komenan: Division of Surgical Oncology, Department of Surgery
Mohammad Atefi: University of California, Los Angeles (UCLA)
Begoña Comin-Anduix: Division of Surgical Oncology, Department of Surgery
Matteo Pellegrini: Cell, and Developmental Biology, University of California, Los Angeles (UCLA)
Alistair J. Cochran: University of California, Los Angeles (UCLA)
Robert L. Modlin: University of California, Los Angeles (UCLA)
Harvey R. Herschman: University of California, Los Angeles (UCLA)
Roger S. Lo: University of California, Los Angeles (UCLA)
William H. McBride: University of California, Los Angeles (UCLA)
Tatiana Segura: University of California, Los Angeles (UCLA)
Antoni Ribas: University of California, Los Angeles (UCLA)

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: Abstract 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) phosphorylation 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.

Date: 2016
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DOI: 10.1038/ncomms12348

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