title: Combination therapy of melanoma using kinase inhibitors.
abstract: OBJECTIVE
  Treatment options for metastatic melanoma depend on the clinical course of the disease and the molecular profile such as mutations of the BRAF gene. In this article, we review the current state of targeted therapy with kinase inhibitors.
  
  
  RESULTS
  Despite major advancements in targeted therapy of metastatic melanoma, most patients relapse and show progressive disease after 5-7 months with single inhibition of BRAF or MEK. Acquired resistance is virtually universal and mediated by diverse mitogen-activated protein kinase-dependent or independent mechanisms. Recent evidence favours concurrent targeting of BRAF and MEK in patients with BRAFV600-mutated melanoma instead of BRAF inhibitor monotherapy. The combination delays the onset of acquired resistance, resulting in increased progression-free and overall survival. A growing number of early trials evaluate the efficacy of inhibitors targeting additional pathways such as phospho-inositide 3-kinase/AKT in conjunction with BRAF or MEK. Even though consistent and mature phase III study results are not yet available for these combinations, the repertoire of targeted therapy in metastatic melanoma is wide and promising.
  
  
  CONCLUSIONS
  The short era of single BRAF inhibition in BRAF-mutated melanoma is soon taken over by dual concurrent inhibition of MEK and BRAF.
authors.affiliation: Department of Dermatology and Allergy, Ludwig-Maximilian University, Munich, Germany.
authors.forename: Markus V
authors.initials: MV
authors.lastname: Heppt
authors.forename: Julia K
authors.initials: JK
authors.lastname: Tietze
authors.forename: Saskia A
authors.initials: SA
authors.lastname: Graf
authors.forename: Carola
authors.initials: C
authors.lastname: Berking
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000188:drug therapy*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D009154:Mutation / Q000187:drug effects; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D012878:Skin Neoplasms; D016896:Treatment Outcome; D000096142:Cutaneous Malignant Melanoma
chemical_list: D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases