Cutaneous wound healing through paradoxical MAPK activation by BRAF inhibitors

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.

Autologous micrograft accelerates endogenous wound healing response through ERK-induced cell migration

“…Specifically, transcriptome analysis of AMG-treated fibroblasts clearly showed upregulation of the MAPK/ERK-signaling pathway, suggesting its involvement in the AMG molecular mechanism. It has been previously shown that activation of the ERK signaling cascade is positively involved in WH mainly through its capacity to stimulate cell proliferation (15). On the other hand, recent evidences show the role of the MAPK pathway in the enhancement of cell migration and morphology, angiogenesis (30) and, most importantly, in regulating tissue repair functions in fibroblasts (31).…”

“…Considering the strong AMG treatment ability to promote motility and migration of fibroblasts in vitro, we used the excisional WH mouse model to address whether topical application of AMG would also stimulate the healing capacity of full-thickness dermal wounds in vivo. In parallel, we tested the involvement of the MAPK cascade on in vivo AMG treatment by using the specific MEK inhibitor trametinib (15).…”

“…Modulation of the extracellular signal-regulated kinase (ERK) -signaling pathway, a MAPK subgroup, leads to changes in cell proliferation, differentiation, inflammation and cell migration (13). ERK signaling activity is needed during WH (14) however, its specific downstream function is still controversial: while in some studies the acceleration of cutaneous WH via MAPK cascade activation has been attributed to increased cell proliferation (15), other studies have shown a specific role in cell migration induction (14).…”

Cancer: the dark side of wound healing

“…BRAF inhibitors enhance patient survival, but also stimulate metastasis through ERK/ MAPK activation in RAS mutant melanoma cells [188]. This same drug-induced MAPK activation improves wound healing in mouse models by stimulating keratinocyte hyperproliferation [189].…”

Targeted Therapies: Immunologic Effects and Potential Applications Outside of Cancer

“…Our group has shown that the topical application of an EGFR inhibitor can enhance the immune response to cutaneous vaccination . More recently, the topical application of the BRAF V600E ‐selective inhibitor vemurafenib has shown promise as a treatment to accelerate wound healing through its paradoxical ability to activate the MAPK pathway . Thus, in addition to their use as systemic agents, locally applied targeted therapies may harbor potential for the treatment of diseases affecting accessible epithelial tissues.…”