Cutaneous wound healing through paradoxical MAPK activation by BRAF inhibitors

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; Begoña Comin-Anduix; Matteo Pellegrini; Alistair J Cochran; Robert L Modlin; Harvey R Herschman; Roger S Lo; William H McBride; Tatiana Segura; Antoni Ribas

doi:10.1038/ncomms12348

Cutaneous wound healing through paradoxical MAPK activation by BRAF inhibitors

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

Authors

Helena Escuin-Ordinas¹, Shuoran Li², Michael W Xie³, Lu Sun⁴, Willy Hugo⁴, Rong Rong Huang⁵, Jing Jiao^{6

7}, Felipe Meira de-Faria^{6

8}, Susan Realegeno⁹, Paige Krystofinski¹, Ariel Azhdam¹, Sara Marie D Komenan¹⁰, Mohammad Atefi¹, Begoña Comin-Anduix^{10

11}, Matteo Pellegrini¹², Alistair J Cochran⁵, Robert L Modlin^{4

11}, Harvey R Herschman^{6

7

11}, Roger S Lo^{4

6

11}, William H McBride^{3

10}, Tatiana Segura², Antoni Ribas^{1

6

10

11}

Affiliations

¹ 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.
² Department of Chemical and Biomolecular Engineering, University of California, Los Angeles (UCLA), 7524 Boelter Hall, Los Angeles, California 90095, USA.
³ Division of Experimental Radiation Oncology, Department of Radiation Oncology, University of California, Los Angeles (UCLA), B3-109 CHS, Los Angeles, California 90095, USA.
⁴ 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.
⁵ 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.
⁶ Department of Molecular and Medical Pharmacology, University of California, Los Angeles (UCLA), 329 Boyer Hall, Los Angeles, California 90095, USA.
⁷ Department of Biological Chemistry, University of California, Los Angeles (UCLA), 341 Boyer Hall, Los Angeles, California 90095, USA.
⁸ Department of Structural and Functional Biology, Institute of Biology, University of Campinas - UNICAMP, Campinas, 13083-970 Sao Paulo, Brazil.
⁹ Department of Microbiology, Immunology &Molecular Genetics, University of California, Los Angeles (UCLA), 52-121 CHS, Los Angeles, California 90095, USA.
¹⁰ Division of Surgical Oncology, Department of Surgery, 11-234 and 9-954 Factor Bldg, Los Angeles, California 90095, USA.
¹¹ Jonsson Comprehensive Cancer Center, 10833 Le Conte Ave, Los Angeles, California 90024, USA.
¹² Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles (UCLA), 3000C Terasaki Life Sciences Bldg, Los Angeles, California 90095, USA.

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding