title: Antitumor activity of the ERK inhibitor SCH772984 [corrected] against BRAF mutant, NRAS mutant and wild-type melanoma.
abstract: BACKGROUND
  In melanoma, dysregulation of the MAPK pathway, usually via BRAF(V600) or NRAS(Q61) somatic mutations, leads to constitutive ERK signaling. While BRAF inhibitors are initially effective for BRAF-mutant melanoma, no FDA-approved targeted therapies exist for BRAF-inhibitor-resistant BRAF(V600), NRAS mutant, or wild-type melanoma.
  
  
  METHODS
  The 50% inhibitory concentration (IC50) of SCH772984, a novel inhibitor of ERK1/2, was determined in a panel of 50 melanoma cell lines. Effects on MAPK and AKT signaling by western blotting and cell cycle by flow cytometry were determined.
  
  
  RESULTS
  Sensitivity fell into three groups: sensitive, 50% inhibitory concentration (IC50) < 1 μM; intermediately sensitive, IC50 1-2 μM; and resistant, >2 μM. Fifteen of 21 (71%) BRAF mutants, including 4 with innate vemurafenib resistance, were sensitive to SCH772984. All three (100%) BRAF/NRAS double mutants, 11 of 14 (78%) NRAS mutants and 5 of 7 (71%) wild-type melanomas were sensitive. Among BRAF(V600) mutants with in vitro acquired resistance to vemurafenib, those with MAPK pathway reactivation as the mechanism of resistance were sensitive to SCH772984. SCH772984 caused G1 arrest and induced apoptosis.
  
  
  CONCLUSIONS
  Combining vemurafenib and SCH722984 in BRAF mutant melanoma was synergistic in a majority of cell lines and significantly delayed the onset of acquired resistance in long term in vitro assays. Therefore, SCH772984 may be clinically applicable as a treatment for non-BRAF mutant melanoma or in BRAF-mutant melanoma with innate or acquired resistance, alone or in combination with BRAF inhibitors.
authors.forename: Deborah J L
authors.initials: DJ
authors.lastname: Wong
authors.forename: Lidia
authors.initials: L
authors.lastname: Robert
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Atefi
authors.forename: Amanda
authors.initials: A
authors.lastname: Lassen
authors.forename: Geetha
authors.initials: G
authors.lastname: Avarappatt
authors.forename: Michael
authors.initials: M
authors.lastname: Cerniglia
authors.forename: Earl
authors.initials: E
authors.lastname: Avramis
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tsoi
authors.forename: David
authors.initials: D
authors.lastname: Foulad
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Graeber
authors.forename: Begonya
authors.initials: B
authors.lastname: Comin-Anduix
authors.forename: Ahmed
authors.initials: A
authors.lastname: Samatar
authors.forename: Roger S
authors.initials: RS
authors.lastname: Lo
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles (UCLA), 11-934 Factor Building, Los Angeles, CA, USA. aribas@mednet.ucla.edu.
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
mesh_terms: D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D058990:Molecular Targeted Therapy; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D000077484:Vemurafenib
chemical_list: D007191:Indazoles; D007211:Indoles; D008565:Membrane Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; C587178:SCH772984; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human