title: Proteomics approaches to understanding mitogen-activated protein kinase inhibitor resistance in melanoma.
abstract: OBJECTIVE
  BRAF inhibitors achieve outstanding clinical response rates in BRAF-mutated melanoma patients but therapeutic resistance is common. Although combinatorial targeted therapy has recently improved patient survival, resistance still occurs, which might be because of the plasticity and heterogeneity of melanoma. Proteomics complements the mostly genomics-based approaches used so far to gain additional insights into the pathophysiological mechanisms driving melanoma progression under treatment.
  
  
  RESULTS
  Few proteomics studies have investigated mitogen-activated protein kinase inhibitor (MAPKi) resistance. Three technologies have been described: shotgun analysis, pressure cycling technology-sequential window acquisition of all theoretical masses (which offers an optimized protein extraction by the pressure cycling technology), and selected reaction monitoring for selected candidate evaluation. Preliminary data demonstrate that BRAFi resistance might be associated with enhanced expression of the lysosomal compartment, cell adhesion, and epithelial-mesenchymal transformation. Melanoma cells change their phenotypes in response to targeted therapy with MAPKi from a proliferative to an invasive state gaining epithelial-mesenchymal transformation features, which are associated with drug resistance.
  
  
  CONCLUSIONS
  Performing proteomics may lead to an enhanced understanding of the underlying mechanisms of MAPKi resistance and might offer new insights for rational therapies. Selected reaction monitoring can be used to evaluate predictive or pharmacodynamic biomarkers for tracking therapeutic responses and identifying early features of resistance.
authors.affiliation: aDepartment of Dermatology, Medical University of Vienna, Vienna, Austria bInstitute of Molecular Systems Biology, ETH Zurich, Switzerland cDepartment of Dermatology, University of Zurich Hospital, University of Zurich, Zurich, Switzerland.
authors.forename: Verena
authors.initials: V
authors.lastname: Paulitschke
authors.forename: Ossia
authors.initials: O
authors.lastname: Eichhoff
authors.forename: Phil F
authors.initials: PF
authors.lastname: Cheng
authors.forename: Mitchell P
authors.initials: MP
authors.lastname: Levesque
authors.forename: Christoph
authors.initials: C
authors.lastname: Höller
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D000074324:Ipilimumab; D020935:MAP Kinase Signaling System / Q000187:drug effects; D013058:Mass Spectrometry; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D040901:Proteomics / Q000379:methods; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013449:Sulfonamides / Q000627:therapeutic use; D000077484:Vemurafenib
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D007211:Indoles; D000074324:Ipilimumab; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases