title: A proliferative melanoma cell phenotype is responsive to RAF/MEK inhibition independent of BRAF mutation status.
abstract: Oncogenic mutations within the MAPK pathway are frequent in melanoma, and targeting of MAPK signaling has yielded spectacular responses in a significant number of patients that last for several months before relapsing. We investigated the effects of two different inhibitors of MAPK signaling in proliferative and invasive melanoma cell cultures with various mutations in the MAPK pathway. Proliferative melanoma cells were more susceptible to pathway inhibition than invasive phenotype cells, irrespective of BRAF mutation status, while invasive phenotype cell response was dependent on BRAF mutation status. Critically, MAPK pathway inhibition of proliferative phenotype cells resulted in acquisition of invasive phenotype characteristics. These results show that melanoma cell phenotype is an important factor in MAPK pathway inhibition response. This suggests that while current therapeutic strategies target proliferative melanoma cells, future approaches should also account for the invasive phenotype population.
authors.affiliation: Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Marie C
authors.initials: MC
authors.lastname: Zipser
authors.forename: Ossia M
authors.initials: OM
authors.lastname: Eichhoff
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Widmer
authors.forename: Natalie C
authors.initials: NC
authors.lastname: Schlegel
authors.forename: Nicola L
authors.initials: NL
authors.lastname: Schoenewolf
authors.forename: Darrin
authors.initials: D
authors.lastname: Stuart
authors.forename: Weihua
authors.initials: W
authors.lastname: Liu
authors.forename: Humphrey
authors.initials: H
authors.lastname: Gardner
authors.forename: Paul D
authors.initials: PD
authors.lastname: Smith
authors.forename: Paolo
authors.initials: P
authors.lastname: Nuciforo
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.forename: Keith S
authors.initials: KS
authors.lastname: Hoek
mesh_terms: D000328:Adult; D000368:Aged; D049109:Cell Proliferation; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D046228:Microarray Analysis; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009361:Neoplasm Invasiveness; D010641:Phenotype; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D048490:raf Kinases / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048490:raf Kinases; D020929:Mitogen-Activated Protein Kinase Kinases