title: Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma.
abstract: Increased expression of the Microphthalmia-associated transcription factor (MITF) contributes to melanoma progression and resistance to BRAF pathway inhibition. Here we show that the lack of MITF is associated with more severe resistance to a range of inhibitors, while its presence is required for robust drug responses. Both in primary and acquired resistance, MITF levels inversely correlate with the expression of several activated receptor tyrosine kinases, most frequently AXL. The MITF-low/AXL-high/drug-resistance phenotype is common among mutant BRAF and NRAS melanoma cell lines. The dichotomous behaviour of MITF in drug response is corroborated in vemurafenib-resistant biopsies, including MITF-high and -low clones in a relapsed patient. Furthermore, drug cocktails containing AXL inhibitor enhance melanoma cell elimination by BRAF or ERK inhibition. Our results demonstrate that a low MITF/AXL ratio predicts early resistance to multiple targeted drugs, and warrant clinical validation of AXL inhibitors to combat resistance of BRAF and NRAS mutant MITF-low melanomas.
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
authors.forename: Judith
authors.initials: J
authors.lastname: Müller
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
authors.forename: Oscar
authors.initials: O
authors.lastname: Krijgsman
authors.affiliation: Division of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California, University of California, Los Angeles (UCLA), 10833 Le Conte Avenue, Los Angeles, California 90095-1750, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tsoi
authors.affiliation: Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles (UCLA), 10833 Le Conte Avenue, Los Angeles, California 90095-7227, USA.
authors.forename: Lidia
authors.initials: L
authors.lastname: Robert
authors.affiliation: Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles (UCLA), 10833 Le Conte Avenue, Los Angeles, California 90095-7227, USA.
authors.forename: Willy
authors.initials: W
authors.lastname: Hugo
authors.affiliation: Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles (UCLA), 10833 Le Conte Avenue, Los Angeles, California 90095-7227, USA.
authors.forename: Chunying
authors.initials: C
authors.lastname: Song
authors.affiliation: Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles (UCLA), 10833 Le Conte Avenue, Los Angeles, California 90095-7227, USA.
authors.forename: Xiangju
authors.initials: X
authors.lastname: Kong
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Possik
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
authors.forename: Paulien D M
authors.initials: PD
authors.lastname: Cornelissen-Steijger
authors.affiliation: Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
authors.forename: Marnix H
authors.initials: MH
authors.lastname: Geukes Foppen
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
authors.forename: Kristel
authors.initials: K
authors.lastname: Kemper
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Headington, Oxford OX3 7DQ, UK.
authors.forename: Colin R
authors.initials: CR
authors.lastname: Goding
authors.affiliation: Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Ultan
authors.initials: U
authors.lastname: McDermott
authors.affiliation: Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Blank
authors.affiliation: Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
authors.forename: John
authors.initials: J
authors.lastname: Haanen
authors.affiliation: 1] Division of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California, University of California, Los Angeles (UCLA), 10833 Le Conte Avenue, Los Angeles, California 90095-1750, USA [2] UCLA Metabolomics Center, Crump Institute for Molecular Imaging, California Nanosystems Institute, UCLA, 570 Westwood Plaza, Building 114, Los Angeles, California 90095-7227, USA [3] Jonsson Comprehensive Cancer Center (JCCC), 8-684 Factor Building, Los Angeles, California 90095-1781, USA.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Graeber
authors.affiliation: 1] Division of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California, University of California, Los Angeles (UCLA), 10833 Le Conte Avenue, Los Angeles, California 90095-1750, USA [2] Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles (UCLA), 10833 Le Conte Avenue, Los Angeles, California 90095-7227, USA [3] Jonsson Comprehensive Cancer Center (JCCC), 8-684 Factor Building, Los Angeles, California 90095-1781, USA.
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.affiliation: 1] Division of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California, University of California, Los Angeles (UCLA), 10833 Le Conte Avenue, Los Angeles, California 90095-1750, USA [2] Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles (UCLA), 10833 Le Conte Avenue, Los Angeles, California 90095-7227, USA [3] Jonsson Comprehensive Cancer Center (JCCC), 8-684 Factor Building, Los Angeles, California 90095-1781, USA.
authors.forename: Roger S
authors.initials: RS
authors.lastname: Lo
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Peeper
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics* / Q000378:metabolism; D010091:Oximes / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D001549:Benzamides; D007093:Imidazoles; D007211:Indoles; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; C550356:N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; D010091:Oximes; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011728:Pyridones; D011743:Pyrimidines; D011744:Pyrimidinones; D013449:Sulfonamides; D000077484:Vemurafenib; C560077:trametinib; D000068877:Imatinib Mesylate; D020794:Receptor Protein-Tyrosine Kinases; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; C561627:dabrafenib; D000094963:Axl Receptor Tyrosine Kinase