title: Association between acquired resistance to PLX4032 (vemurafenib) and ATP-binding cassette transporter expression.
abstract: BACKGROUND
  Various kinase inhibitors are known to be ATP-binding cassette (ABC) transporter substrates and resistance acquisition to kinase inhibitors has been associated to increased ABC transporter expression. Here, we investigated the role of the ABC transporters ABCB1, ABCC1, and ABCG2 during melanoma cell resistance acquisition to the V600-mutant BRAF inhibitors PLX4032 (vemurafenib) and PLX4720. PLX4032 had previously been shown to interfere with ABCB1 and ABCG2. PLX4720 had been demonstrated to interact with ABCB1 but to a lower extent than PLX4032.
  
  
  RESULTS
  PLX4032 and PLX4720 affected ABCC1- and ABCG2-mediated drug transport in a similar fashion. In a panel of 16 V600E BRAF-mutated melanoma cell lines consisting of four parental cell lines and their sub-lines with acquired resistance to PLX4032, PLX4720, vincristine (cytotoxic ABCB1 and ABCC1 substrate), or mitoxantrone (cytotoxic ABCG2 substrate), we detected enhanced ABC transporter expression in 4/4 cytotoxic ABC transporter substrate-resistant, 3/4 PLX4720-resistant, and 1/4 PLX4032-resistant melanoma cell lines.
  
  
  CONCLUSIONS
  PLX4032 has the potential to induce ABC transporter expression but this potential is lower than that of PLX4720 or cytotoxic ABC transporter substrates. Since ABC transporters confer multi-drug resistance, this is of relevance for the design of next-line therapies.
authors.forename: Martin
authors.initials: M
authors.lastname: Michaelis
authors.forename: Florian
authors.initials: F
authors.lastname: Rothweiler
authors.forename: Thomas
authors.initials: T
authors.lastname: Nerreter
authors.forename: Marijke
authors.initials: M
authors.lastname: van Rikxoort
authors.forename: Richard
authors.initials: R
authors.lastname: Zehner
authors.forename: Wilhelm G
authors.initials: WG
authors.lastname: Dirks
authors.forename: Michael
authors.initials: M
authors.lastname: Wiese
authors.affiliation: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Paul Ehrlich-Str, 40, Frankfurt am Main 60596, Germany. Cinatl@em.uni-frankfurt.de.
authors.forename: Jindrich
authors.initials: J
authors.lastname: Cinatl
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000187:drug effects / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D008545:Melanoma / Q000201:enzymology / Q000235:genetics; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D009363:Neoplasm Proteins / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000201:enzymology / Q000235:genetics; D013449:Sulfonamides / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors; D000077484:Vemurafenib
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D007211:Indoles; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D013449:Sulfonamides; D000077484:Vemurafenib; C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; C528407:PLX 4720; C482119:BRAF protein, human; C421109:multidrug resistance-associated protein 1