title: Preexisting MEK1P124 mutations diminish response to BRAF inhibitors in metastatic melanoma patients.
abstract: BACKGROUND
  MEK1 mutations in melanoma can confer resistance to BRAF inhibitors, although preexisting MEK1(P124) mutations do not preclude clinical responses. We sought to determine whether recurrent, preexisting MEK1(P124) mutations affected clinical outcome in BRAF inhibitor-treated patients with melanoma.
  
  
  METHODS
  Data from four published datasets were analyzed to determine whether preexisting MEK1(P124) mutations affect radiologic response or progression-free survival (PFS) in patients with BRAF(V600)-mutant metastatic melanoma treated with vemurafenib or dabrafenib. The effects of MEK1(P124) mutations on MAPK pathway activity and response to BRAF inhibition were also investigated in a series of cell models.
  
  
  RESULTS
  In a pooled analysis of 123 patients, the presence of a pretreatment MEK1(P124) mutation (N = 12, 10%) was associated with a poorer RECIST response (33% vs. 72% in MEK1(P124Q/S) vs. MEK1(P124) wild-type, P = 0.018), and a shorter PFS (median 3.1 vs. 4.8 months, P = 0.004). Furthermore, MEK1(P124Q/S) mutations were shown to have independent kinase activity and introduction of these mutations into a BRAF-mutant melanoma cell line diminished inhibition of ERK phosphorylation by dabrafenib and enhanced clonogenic survival in the presence of dabrafenib compared with cells ectopically expressing wild-type MEK1. Consistent with these data, two BRAF-mutant cell lines with endogenous MEK1(P124) mutations showed intermediate sensitivity to dabrafenib, but were highly sensitive to downstream inhibition of MEK or ERK.
  
  
  CONCLUSIONS
  Taken together, our data indicate that preexisting MEK1(P124) mutations are associated with a reduced response to BRAF inhibitor therapy and identify a subset of patients with BRAF-mutant melanoma likely to benefit from combination therapies involving MEK or ERK inhibitors.
authors.affiliation: Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead, New South Wales, Australia. Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, New South Wales, Australia. Melanoma Institute Australia, Sydney, New South Wales, Australia.
authors.forename: Matteo S
authors.initials: MS
authors.lastname: Carlino
authors.affiliation: Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead, New South Wales, Australia. Australian School of Advanced Medicine, Macquarie University, New South Wales, Australia.
authors.forename: Carina
authors.initials: C
authors.lastname: Fung
authors.affiliation: Australian School of Advanced Medicine, Macquarie University, New South Wales, Australia.
authors.forename: Hamideh
authors.initials: H
authors.lastname: Shahheydari
authors.affiliation: Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead, New South Wales, Australia.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Todd
authors.affiliation: Australian School of Advanced Medicine, Macquarie University, New South Wales, Australia.
authors.forename: Suzanah C
authors.initials: SC
authors.lastname: Boyd
authors.affiliation: Australian School of Advanced Medicine, Macquarie University, New South Wales, Australia.
authors.forename: Mal
authors.initials: M
authors.lastname: Irvine
authors.affiliation: The Kinghorn Cancer Centre, Cancer Research Program, Garvan Institute of Medical Research, Sydney, Australia.
authors.forename: Adnan M
authors.initials: AM
authors.lastname: Nagrial
authors.affiliation: Melanoma Institute Australia, Sydney, New South Wales, Australia. Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia. Department of Tissue Pathology and Diagnostic Oncology Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.affiliation: Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead, New South Wales, Australia. Australian School of Advanced Medicine, Macquarie University, New South Wales, Australia. Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
authors.affiliation: Melanoma Institute Australia, Sydney, New South Wales, Australia. Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.affiliation: Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead, New South Wales, Australia. Australian School of Advanced Medicine, Macquarie University, New South Wales, Australia. Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia. helen.rizos@mq.edu.au.
authors.forename: Helen
authors.initials: H
authors.lastname: Rizos
mesh_terms: D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D007211:Indoles / Q000008:administration & dosage; D048369:MAP Kinase Kinase 1 / Q000235:genetics*; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D010091:Oximes / Q000008:administration & dosage; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D013449:Sulfonamides / Q000008:administration & dosage; D000077484:Vemurafenib
chemical_list: D007093:Imidazoles; D007211:Indoles; D010091:Oximes; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C561627:dabrafenib