title: MAPK Pathway Inhibitors Sensitize BRAF-Mutant Melanoma to an Antibody-Drug Conjugate Targeting GPNMB.
abstract: OBJECTIVE
  To determine if BRAF and/or MEK inhibitor-induced GPNMB expression renders melanomas sensitive to CDX-011, an antibody-drug conjugate targeting GPNMB.
  
  
  METHODS
  The Cancer Genome Atlas melanoma dataset was interrogated for a panel of MITF-regulated melanosomal differentiation antigens, including GPNMB. BRAF-mutant melanoma cell lines treated with BRAF or MEK inhibitors were assessed for GPNMB expression by RT-qPCR, immunoblot, and FACS analyses. Transient siRNA-mediated knockdown approaches were used to determine if MITF is requirement for treatment-induced GPNMB upregulation. GPNMB expression was analyzed in serial biopsies and serum samples from patients with melanoma taken before, during, and after disease progression on MAPK inhibitor treatment. Subcutaneous injections were performed to test the efficacy of MAPK inhibitors alone, CDX-011 alone, or their combination in suppressing melanoma growth.
  
  
  RESULTS
  A MITF-dependent melanosomal differentiation signature is associated with poor prognosis in patients with this disease. MITF is increased following BRAF and MEK inhibitor treatment and induces the expression of melanosomal differentiation genes, including GPNMB. GPNMB is expressed at the cell surface in MAPK inhibitor-treated melanoma cells and is also elevated in on-treatment versus pretreatment biopsies from melanoma patients receiving MAPK pathway inhibitors. Combining BRAF and/or MEK inhibitors with CDX-011, an antibody-drug conjugate targeting GPNMB, is effective in causing melanoma regression in preclinical animal models and delays the recurrent melanoma growth observed with MEK or BRAF/MEK inhibitor treatment alone.
  
  
  CONCLUSIONS
  The combination of MAPK pathway inhibitors with an antibody-drug conjugate targeting GPNMB is an effective therapeutic option for patients with melanoma. Clin Cancer Res; 22(24); 6088-98. ©2016 AACR.
authors: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada.|Department of Medicine, McGill University, Montréal, Québec, Canada.
authors: April A N
authors: AA
authors: Rose
authors: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada.|Department of Medicine, McGill University, Montréal, Québec, Canada.
authors: Matthew G
authors: MG
authors: Annis
authors: Department of Biophysics, UT Southwestern, Dallas, Texas.
authors: Dennie T
authors: DT
authors: Frederick
authors: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada.|Department of Medicine, McGill University, Montréal, Québec, Canada.
authors: Marco
authors: M
authors: Biondini
authors: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada.|Department of Medicine, McGill University, Montréal, Québec, Canada.
authors: Zhifeng
authors: Z
authors: Dong
authors: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Lawrence
authors: L
authors: Kwong
authors: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Lynda
authors: L
authors: Chin
authors: Celldex Therapeutics, Hampton, New Jersey.
authors: Tibor
authors: T
authors: Keler
authors: Celldex Therapeutics, Hampton, New Jersey.
authors: Thomas
authors: T
authors: Hawthorne
authors: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada.|Department of Biochemistry, McGill University, Montréal, Québec, Canada.
authors: Ian R
authors: IR
authors: Watson
authors: Department of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts.
authors: Keith T
authors: KT
authors: Flaherty
authors: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada. peter.siegel@mcgill.ca.|Department of Medicine, McGill University, Montréal, Québec, Canada.|Department of Biochemistry, McGill University, Montréal, Québec, Canada.
authors: Peter M
authors: PM
authors: Siegel
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics; D000096142:Cutaneous Malignant Melanoma
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C503042:GPNMB protein, human; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D047428:Protein Kinase Inhibitors; C551271:glembatumumab vedotin; D048493:Proto-Oncogene Proteins B-raf