Cutaneous wound healing through paradoxical MAPK activation by BRAF inhibitors.

Helena Escuin-Ordinas,Paige Krystofinski,Susan Realegeno,Alistair J Cochran,Antoni Ribas,Matteo Pellegrini,Sara Marie D Komenan,Harvey R Herschman,Jing Jiao,Tatiana Segura,Willy Hugo,Roger S Lo,Michael W Xie,William H Mcbride,Shuoran Li,Mohammad Atefi,Robert L Modlin,Felipe Meira De-Faria,Begoña Comı́n-Anduix ,Ariel M Azhdam ,Rong Huang ,Lingyun Sun

doi:10.1038/ncomms12348

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.

Highlights

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
In our studies we demonstrate that vemurafenib promotes both proliferative and migratory effects on adult human epithelial keratinocytes (HEKa) in vitro by inducing phosphorylation of pErk and activation of the proliferative marker Ki67
We tested whether the skin hyperproliferative side effects of BRAF inhibitors can be exploited to accelerate skin wound healing by inducing paradoxical MAPK activation

Summary

Introduction

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. 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. In this study we show how we can take advantage of the mechanistic understanding of the skin hyperproliferative side effects of BRAF inhibitors to accelerate skin wound healing by inducing paradoxical MAPK activation in keratinocytes, which are the predominant cells in the epidermis. We hypothesized that paradoxical MAPK activation induced by a BRAF inhibitor in these BRAF wild-type cells would accelerate cutaneous wound healing. Topical BRAF inhibitors may be used to improve the healing of acute skin wounds

Methods

Results

Conclusion