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Updated: Mar 17, 2026

The Three-Dimensional Human Skin Reconstruct Model: a Tool to Study Normal Skin and Melanoma Progression
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Cutaneous wound healing through paradoxical MAPK activation by BRAF inhibitors

Helena Escuin-Ordinas1, Shuoran Li2, Michael W Xie3

  • 1Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles (UCLA), 14-635 Factor Bldg, 10833 Le Conte Avenue, Los Angeles, California 90095, USA.

Nature Communications
|August 2, 2016
PubMed

Insights

Topical BRAF inhibitors, like vemurafenib, accelerate skin wound healing by promoting keratinocyte migration and proliferation. Co-administration with MEK inhibitors reverses this beneficial effect on wound repair.

Area of Science:

  • Dermatology
  • Oncology
  • Molecular Biology

Background:

  • BRAF inhibitors treat BRAF(V600)-mutated melanoma.
  • A common side effect is skin hyperproliferation due to paradoxical MAPK pathway activation in BRAF wild-type cells.
  • MEK inhibitors mitigate these skin toxicities by blocking MAPK activation.

Purpose of the Study:

  • To investigate the potential of topical BRAF inhibitors to accelerate skin wound healing.
  • To elucidate the mechanism behind vemurafenib-induced skin wound healing.
  • To assess the safety of topical BRAF inhibitors regarding skin cancer development.

Main Methods:

  • Utilized human keratinocytes in vitro to study cell proliferation and migration.
  • Employed two distinct mouse models for cutaneous wound healing.
  • Administered topical vemurafenib and co-administered MEK inhibitors.

Main Results:

  • Vemurafenib treatment accelerated skin wound healing in mice.
  • This acceleration was mediated by ERK phosphorylation and cell cycle progression in keratinocytes.
  • Co-administration of a MEK inhibitor negated the wound-healing benefits of vemurafenib.
  • Topical vemurafenib did not increase squamous cell carcinoma incidence in mice.

Conclusions:

  • Topical BRAF inhibitors, such as vemurafenib, can accelerate skin wound healing.
  • The pro-healing effect involves paradoxical MAPK pathway activation.
  • Topical BRAF inhibitors may offer a novel therapeutic strategy for promoting skin wound repair without increasing skin cancer risk.

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