Cutaneous Wound Healing Through Paradoxical MAPK Activation by BRAF Inhibitors

Overview

Journal Nat Commun

Specialty Biology

Date 2016 Aug 2

PMID 27476449

Citations 29

Authors

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

Begona Comin-Anduix

Matteo Pellegrini

Alistair J Cochran

Robert L Modlin

Harvey R Herschman

Roger S Lo

William H McBride

Tatiana Segura

Antoni Ribas

Affiliations

Soon will be listed here.

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.

Citing Articles

The paradoxical activity of BRAF inhibitors: potential use in wound healing.

Karhana S, Samim M, Nidhi , Khan M Arch Dermatol Res. 2025; 317(1):311.

PMID: 39873776 DOI: 10.1007/s00403-024-03785-5.

BRAF inhibitors enhance erythropoiesis and treat anemia through paradoxical activation of MAPK signaling.

Wu S, Deng Y, Sun H, Liu X, Zhou S, Zhao H Signal Transduct Target Ther. 2024; 9(1):338.

PMID: 39617757 PMC: 11609275. DOI: 10.1038/s41392-024-02033-6.

Cratylia mollis lectin reduces inflammatory burden induced by multidrug-resistant Staphylococcus aureus in diabetic wounds.

Dos Santos Silva L, Dos Santos Castelo Branco S, Silva I, Paiva M, Vila Nova B, de Matos Chaves Lima C Histochem Cell Biol. 2024; 163(1):13.

PMID: 39611987 DOI: 10.1007/s00418-024-02330-9.

Off-targets of BRAF inhibitors disrupt endothelial signaling and vascular barrier function.

Bromberger S, Zadorozhna Y, Ressler J, Holzner S, Nawrocki A, Zila N Life Sci Alliance. 2024; 7(8).

PMID: 38839106 PMC: 11153892. DOI: 10.26508/lsa.202402671.

Targeting Signalling Pathways in Chronic Wound Healing.

Bonnici L, Suleiman S, Schembri-Wismayer P, Cassar A Int J Mol Sci. 2024; 25(1).

PMID: 38203220 PMC: 10779022. DOI: 10.3390/ijms25010050.

References

Inkeles M, Scumpia P, Swindell W, Lopez D, Teles R, Graeber T . Comparison of molecular signatures from multiple skin diseases identifies mechanisms of immunopathogenesis. J Invest Dermatol. 2014; 135(1):151-159. PMC: 4268388. DOI: 10.1038/jid.2014.352. View

Deonarine K, Panelli M, Stashower M, Jin P, Smith K, Slade H . Gene expression profiling of cutaneous wound healing. J Transl Med. 2007; 5:11. PMC: 1804259. DOI: 10.1186/1479-5876-5-11. View

Gorodetsky R, McBride W, Withers H . Assay of radiation effects in mouse skin as expressed in wound healing. Radiat Res. 1988; 116(1):135-44. View

Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O . RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012; 366(3):207-15. PMC: 3724537. DOI: 10.1056/NEJMoa1105358. View

Jacomy M, Venturini T, Heymann S, Bastian M . ForceAtlas2, a continuous graph layout algorithm for handy network visualization designed for the Gephi software. PLoS One. 2014; 9(6):e98679. PMC: 4051631. DOI: 10.1371/journal.pone.0098679. View

Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg S . TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 2013; 14(4):R36. PMC: 4053844. DOI: 10.1186/gb-2013-14-4-r36. View

Eyers P, Cohen P, Goedert M, Boyle F, Hewitt N, Plant H . Paradoxical activation of Raf by a novel Raf inhibitor. Chem Biol. 1999; 6(8):559-68. DOI: 10.1016/s1074-5521(99)80088-x. View

Balmain A, Ramsden M, Bowden G, Smith J . Activation of the mouse cellular Harvey-ras gene in chemically induced benign skin papillomas. Nature. 1984; 307(5952):658-60. DOI: 10.1038/307658a0. View

Gorodetsky R . The use of fibrin based matrices and fibrin microbeads (FMB) for cell based tissue regeneration. Expert Opin Biol Ther. 2008; 8(12):1831-46. DOI: 10.1517/14712590802494576. View

10.

Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A . ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics. 2009; 25(8):1091-3. PMC: 2666812. DOI: 10.1093/bioinformatics/btp101. View

11.

Poulikakos P, Zhang C, Bollag G, Shokat K, Rosen N . RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 2010; 464(7287):427-30. PMC: 3178447. DOI: 10.1038/nature08902. View

12.

Hatzivassiliou G, Song K, Yen I, Brandhuber B, Anderson D, Alvarado R . RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010; 464(7287):431-5. DOI: 10.1038/nature08833. View

13.

Gurtner G, Werner S, Barrandon Y, Longaker M . Wound repair and regeneration. Nature. 2008; 453(7193):314-21. DOI: 10.1038/nature07039. View

14.

Swindell W, Johnston A, Voorhees J, Elder J, Gudjonsson J . Dissecting the psoriasis transcriptome: inflammatory- and cytokine-driven gene expression in lesions from 163 patients. BMC Genomics. 2013; 14:527. PMC: 3751090. DOI: 10.1186/1471-2164-14-527. View

15.

Sun B, Siprashvili Z, Khavari P . Advances in skin grafting and treatment of cutaneous wounds. Science. 2014; 346(6212):941-5. DOI: 10.1126/science.1253836. View

16.

Abel E, Angel J, Kiguchi K, DiGiovanni J . Multi-stage chemical carcinogenesis in mouse skin: fundamentals and applications. Nat Protoc. 2009; 4(9):1350-62. PMC: 3213400. DOI: 10.1038/nprot.2009.120. View

17.

Hanzelmann S, Castelo R, Guinney J . GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics. 2013; 14:7. PMC: 3618321. DOI: 10.1186/1471-2105-14-7. View

18.

Fitsialos G, Chassot A, Turchi L, Dayem M, Lebrigand K, Moreilhon C . Transcriptional signature of epidermal keratinocytes subjected to in vitro scratch wounding reveals selective roles for ERK1/2, p38, and phosphatidylinositol 3-kinase signaling pathways. J Biol Chem. 2007; 282(20):15090-102. DOI: 10.1074/jbc.M606094200. View

19.

Ishikawa T, Jain N, Herschman H . Cox-2 gene expression in chemically induced skin papillomas cannot predict subsequent tumor fate. Mol Oncol. 2010; 4(4):347-56. PMC: 2917485. DOI: 10.1016/j.molonc.2010.06.004. View

20.

Wu Y, Chen L, Scott P, Tredget E . Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells. 2007; 25(10):2648-59. DOI: 10.1634/stemcells.2007-0226. View