title: Combinatorial drug screening and molecular profiling reveal diverse mechanisms of intrinsic and adaptive resistance to BRAF inhibition in V600E BRAF mutant melanomas.
abstract: Over half of BRAFV600E melanomas display intrinsic resistance to BRAF inhibitors, in part due to adaptive signaling responses. In this communication we ask whether BRAFV600E melanomas share common adaptive responses to BRAF inhibition that can provide clinically relevant targets for drug combinations. We screened a panel of 12 treatment-naïve BRAFV600E melanoma cell lines with MAP Kinase pathway inhibitors in pairwise combination with 58 signaling inhibitors, assaying for synergistic cytotoxicity. We found enormous diversity in the drug combinations that showed synergy, with no two cell lines having an identical profile. Although the 6 lines most resistant to BRAF inhibition showed synergistic benefit from combination with lapatinib, the signaling mechanisms by which this combination generated synergistic cytotoxicity differed between the cell lines. We conclude that adaptive responses to inhibition of the primary oncogenic driver (BRAFV600E) are determined not only by the primary oncogenic driver but also by diverse secondary genetic and epigenetic changes ("back-seat drivers") and hence optimal drug combinations will be variable. Because upregulation of receptor tyrosine kinases is a major source of drug resistance arising from diverse adaptive responses, we propose that inhibitors of these receptors may have substantial clinical utility in combination with inhibitors of the MAP Kinase pathway.
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, 22908 USA.
authors.forename: Devin G
authors.initials: DG
authors.lastname: Roller
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, 22908 USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Capaldo
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, 22908 USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bekiranov
authors.affiliation: Department of Public Health Sciences, University of Virginia, Charlottesville, VA, 22908 USA.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Mackey
authors.affiliation: Department of Public Health Sciences, University of Virginia, Charlottesville, VA, 22908 USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Conaway
authors.affiliation: Center for Applied Proteomics and Molecular Medicine, School of Systems Biology, College of Science, George Mason University, Manassas, VA 20110, USA.
authors.forename: Emanuel F
authors.initials: EF
authors.lastname: Petricoin
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, 22908 USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gioeli
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, 22908 USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Weber
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D000077341:Lapatinib; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D007211:Indoles; C528407:PLX 4720; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D013449:Sulfonamides; D000077341:Lapatinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF; MAP Kinase; cell signaling; melanoma; therapeutic resistance