title: Protein kinase inhibitors in melanoma.
abstract: BACKGROUND
  The most commonly mutated oncogene identified to date in melanoma is BRAF (∼ 50%), an upstream mediator of the mitogen-activated protein kinase (MAPK) pathway. Recently, BRAF-kinase inhibitors as well as MEK-kinase inhibitors were introduced into the clinics.
  
  
  METHODS
  Substantial Phase II and III clinical trials were searched in patients with advanced melanoma treated with BRAF-kinase inhibitors, MEK-kinase inhibitors and cKIT inhibitors.
  
  
  CONCLUSIONS
  For patients with a BRAF, NRAS or cKIT mutation the treatment with selective, targeted drugs is considered as feasible and results in a high rate of confirmed tumor responses. In patients with BRAF mutation the progression free survival and overall survival is prolonged in patients who were treated with BRAF kinase inhibitors or MEK kinase inhibitors compared to patients receiving chemotherapy with dacarbazine. A major problem is the development of resistance to the inhibitors through multiple different mechanisms. One approach to overcome resistance is to combine BRAF and MEK inhibitors. Treatments with kinase inhibitors are more efficacious than chemotherapies, however, they compete with the newly developed immune checkpoint blockers, and may in future be preferentially applied in second- or x-line.
authors.affiliation: Center for Dermatooncology, Department of Dermatology , Liebermeisterstrasse 20, 72076 Tübingen , Germany.
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Eigentler
authors.forename: Friedegund
authors.initials: F
authors.lastname: Meier
authors.forename: Claus
authors.initials: C
authors.lastname: Garbe
mesh_terms: D019008:Drug Resistance, Neoplasm; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D008545:Melanoma / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors; D012878:Skin Neoplasms / Q000188:drug therapy*
chemical_list: D047428:Protein Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit; D048493:Proto-Oncogene Proteins B-raf; D020930:MAP Kinase Kinase Kinases