title: Cutaneous wound healing through paradoxical MAPK activation by BRAF inhibitors.
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.
authors.affiliation: Division 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.
authors.forename: Helena
authors.initials: H
authors.lastname: Escuin-Ordinas
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of California, Los Angeles (UCLA), 7524 Boelter Hall, Los Angeles, California 90095, USA.
authors.forename: Shuoran
authors.initials: S
authors.lastname: Li
authors.affiliation: Division of Experimental Radiation Oncology, Department of Radiation Oncology, University of California, Los Angeles (UCLA), B3-109 CHS, Los Angeles, California 90095, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Xie
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, Los Angeles (UCLA), 52-121 CHS and 13-942 Factor Bldg, Los Angeles, California 90095, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Sun
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, Los Angeles (UCLA), 52-121 CHS and 13-942 Factor Bldg, Los Angeles, California 90095, USA.
authors.forename: Willy
authors.identifier: 0000-0002-1426-7190
authors.initials: W
authors.lastname: Hugo
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles (UCLA), 924 Westwood Blvd. 730 and 1P-162 CHS, Los Angeles, California 90095, USA.
authors.forename: Rong Rong
authors.initials: RR
authors.lastname: Huang
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles (UCLA), 329 Boyer Hall, Los Angeles, California 90095, USA.|Department of Biological Chemistry, University of California, Los Angeles (UCLA), 341 Boyer Hall, Los Angeles, California 90095, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Jiao
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles (UCLA), 329 Boyer Hall, Los Angeles, California 90095, USA.|Department of Structural and Functional Biology, Institute of Biology, University of Campinas - UNICAMP, Campinas, 13083-970 Sao Paulo, Brazil.
authors.forename: Felipe Meira
authors.identifier: 0000-0002-7875-0691
authors.initials: FM
authors.lastname: de-Faria
authors.affiliation: Department of Microbiology, Immunology &Molecular Genetics, University of California, Los Angeles (UCLA), 52-121 CHS, Los Angeles, California 90095, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Realegeno
authors.affiliation: Division 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.
authors.forename: Paige
authors.initials: P
authors.lastname: Krystofinski
authors.affiliation: Division 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.
authors.forename: Ariel
authors.initials: A
authors.lastname: Azhdam
authors.affiliation: Division of Surgical Oncology, Department of Surgery, 11-234 and 9-954 Factor Bldg, Los Angeles, California 90095, USA.
authors.forename: Sara Marie D
authors.initials: SM
authors.lastname: Komenan
authors.affiliation: Division 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.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Atefi
authors.affiliation: Division of Surgical Oncology, Department of Surgery, 11-234 and 9-954 Factor Bldg, Los Angeles, California 90095, USA.|Jonsson Comprehensive Cancer Center, 10833 Le Conte Ave, Los Angeles, California 90024, USA.
authors.forename: Begoña
authors.initials: B
authors.lastname: Comin-Anduix
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles (UCLA), 3000C Terasaki Life Sciences Bldg, Los Angeles, California 90095, USA.
authors.forename: Matteo
authors.initials: M
authors.lastname: Pellegrini
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles (UCLA), 924 Westwood Blvd. 730 and 1P-162 CHS, Los Angeles, California 90095, USA.
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Cochran
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, Los Angeles (UCLA), 52-121 CHS and 13-942 Factor Bldg, Los Angeles, California 90095, USA.|Jonsson Comprehensive Cancer Center, 10833 Le Conte Ave, Los Angeles, California 90024, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Modlin
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles (UCLA), 329 Boyer Hall, Los Angeles, California 90095, USA.|Department of Biological Chemistry, University of California, Los Angeles (UCLA), 341 Boyer Hall, Los Angeles, California 90095, USA.|Jonsson Comprehensive Cancer Center, 10833 Le Conte Ave, Los Angeles, California 90024, USA.
authors.forename: Harvey R
authors.initials: HR
authors.lastname: Herschman
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, Los Angeles (UCLA), 52-121 CHS and 13-942 Factor Bldg, Los Angeles, California 90095, USA.|Department of Molecular and Medical Pharmacology, University of California, Los Angeles (UCLA), 329 Boyer Hall, Los Angeles, California 90095, USA.|Jonsson Comprehensive Cancer Center, 10833 Le Conte Ave, Los Angeles, California 90024, USA.
authors.forename: Roger S
authors.initials: RS
authors.lastname: Lo
authors.affiliation: Division of Experimental Radiation Oncology, Department of Radiation Oncology, University of California, Los Angeles (UCLA), B3-109 CHS, Los Angeles, California 90095, USA.|Division of Surgical Oncology, Department of Surgery, 11-234 and 9-954 Factor Bldg, Los Angeles, California 90095, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: McBride
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of California, Los Angeles (UCLA), 7524 Boelter Hall, Los Angeles, California 90095, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Segura
authors.affiliation: Division 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.|Department of Molecular and Medical Pharmacology, University of California, Los Angeles (UCLA), 329 Boyer Hall, Los Angeles, California 90095, USA.|Division of Surgical Oncology, Department of Surgery, 11-234 and 9-954 Factor Bldg, Los Angeles, California 90095, USA.|Jonsson Comprehensive Cancer Center, 10833 Le Conte Ave, Los Angeles, California 90024, USA.
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
mesh_terms: D000287:Administration, Topical; D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects / Q000473:pathology; D002273:Carcinogens / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000188:drug therapy / Q000453:epidemiology / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D015994:Incidence; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D015603:Keratinocytes; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000453:epidemiology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D011728:Pyridones / Q000494:pharmacology / Q000627:therapeutic use; D011744:Pyrimidinones / Q000494:pharmacology / Q000627:therapeutic use; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000139:chemically induced / Q000188:drug therapy / Q000453:epidemiology / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D000077484:Vemurafenib; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D002273:Carcinogens; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D013449:Sulfonamides; D000077484:Vemurafenib; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases