Cutaneous wound healing through paradoxical MAPK activation by BRAF inhibitors

Nat Commun. 2016 Aug 1;7:12348. doi: 10.1038/ncomms12348.

Abstract

BRAF inhibitors are highly effective therapies for the treatment of BRAF(V600)-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Topical
  • Animals
  • Carcinogenesis / drug effects
  • Carcinogenesis / pathology
  • Carcinogens / toxicity
  • Carcinoma, Squamous Cell / chemically induced
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / epidemiology
  • Carcinoma, Squamous Cell / pathology
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Female
  • Humans
  • Incidence
  • Indoles / pharmacology
  • Indoles / therapeutic use
  • Keratinocytes
  • MAP Kinase Signaling System / drug effects*
  • Mice
  • Mice, Inbred BALB C
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism
  • Neoplasms, Experimental / chemically induced
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / epidemiology
  • Neoplasms, Experimental / pathology
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Pyridones / pharmacology
  • Pyridones / therapeutic use
  • Pyrimidinones / pharmacology
  • Pyrimidinones / therapeutic use
  • Skin / drug effects*
  • Skin / metabolism
  • Skin / pathology
  • Skin Neoplasms / chemically induced
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / epidemiology
  • Skin Neoplasms / pathology
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use
  • Treatment Outcome
  • Vemurafenib
  • Wound Healing / drug effects*

Substances

  • Carcinogens
  • Indoles
  • Protein Kinase Inhibitors
  • Pyridones
  • Pyrimidinones
  • Sulfonamides
  • Vemurafenib
  • trametinib
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase Kinases