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Nat Commun. 2014 Dec 15;5:5712. doi: 10.1038/ncomms6712.

Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma.

Author information

  • 1Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
  • 2Division 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.
  • 3Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles (UCLA), 10833 Le Conte Avenue, Los Angeles, California 90095-7227, USA.
  • 4Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
  • 5Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Headington, Oxford OX3 7DQ, UK.
  • 6Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
  • 71] 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.
  • 81] 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.

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.

Comment in

PMID:
25502142
PMCID:
PMC4428333
DOI:
10.1038/ncomms6712
[PubMed - indexed for MEDLINE]
Free PMC Article

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