title: The role of MEK inhibitors in the treatment of metastatic melanoma.
abstract: OBJECTIVE
  BRAF and NRAS mutations can exert an oncogenic effect and are a target for novel therapeutic strategies. Selective MEK inhibitors inhibit growth and induce cell death in BRAF and NRAS mutated melanoma cell lines. The first MEK inhibitor (trametinib) has recently been approved for the treatment of BRAF-mutated metastatic melanoma not previously treated with BRAF inhibitors and several more are in clinical development.
  
  
  RESULTS
  MEK inhibition is associated with improved response rate, progression-free survival, and overall survival in patients with BRAF-mutated metastatic melanoma. Less clinical benefit has been observed in patients previously treated with a BRAF inhibitor compared with BRAF-inhibitor-naïve patients. Data also suggest clinical activity in patients with NRAS-mutated melanoma. Combination therapy with a BRAF inhibitor may improve the efficacy and reduce BRAF-inhibition-associated side effects.
  
  
  CONCLUSIONS
  MEK inhibitors represent a new treatment option in BRAF and NRAS mutated melanoma. As monotherapy, MEK inhibitors appear to provide minimal benefit in patients previously treated with a BRAF inhibitor, so they should be reserved for BRAF-inhibitor-naïve patients. Combined BRAF and MEK inhibition seems to provide a greater benefit than BRAF inhibitor monotherapy. MEK inhibition has also shown efficacy in NRAS-mutated patients, for whom there is no specific targeted therapy.
authors.affiliation: Istituto Nazionale Tunori Fondazione 'G. Pascale', Naples, Italy.
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Grimaldi
authors.forename: Ester
authors.initials: E
authors.lastname: Simeone
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Ascierto
mesh_terms: D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D011728:Pyridones / Q000627:therapeutic use*; D011744:Pyrimidinones / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human