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

Judith Müller; Oscar Krijgsman; Jennifer Tsoi; Lidia Robert; Willy Hugo; Chunying Song; Xiangju Kong; Patricia A Possik; Paulien D M Cornelissen-Steijger; Marnix H Geukes Foppen; Kristel Kemper; Colin R Goding; Ultan McDermott; Christian Blank; John Haanen; Thomas G Graeber; Antoni Ribas; Roger S Lo; Daniel S Peeper

doi:10.1038/ncomms6712

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

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

Authors

Judith Müller¹, Oscar Krijgsman¹, Jennifer Tsoi², Lidia Robert³, Willy Hugo³, Chunying Song³, Xiangju Kong³, Patricia A Possik¹, Paulien D M Cornelissen-Steijger¹, Marnix H Geukes Foppen⁴, Kristel Kemper¹, Colin R Goding⁵, Ultan McDermott⁶, Christian Blank⁴, John Haanen⁴, Thomas G Graeber⁷, Antoni Ribas⁸, Roger S Lo⁸, Daniel S Peeper¹

Affiliations

¹ Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
² 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.
³ 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.
⁴ Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
⁵ Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Headington, Oxford OX3 7DQ, UK.
⁶ Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
⁷ 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.
⁸ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aminopyridines / pharmacology
Animals
Antineoplastic Agents / pharmacology*
Axl Receptor Tyrosine Kinase
Benzamides / pharmacology
Cell Line, Tumor
Drug Resistance, Neoplasm / genetics*
Extracellular Signal-Regulated MAP Kinases / genetics
Extracellular Signal-Regulated MAP Kinases / metabolism
Gene Expression Regulation, Neoplastic*
Humans
Imatinib Mesylate
Imidazoles / pharmacology
Indoles / pharmacology
Melanoma / drug therapy*
Melanoma / genetics
Melanoma / metabolism
Melanoma / pathology
Mice
Microphthalmia-Associated Transcription Factor / genetics*
Microphthalmia-Associated Transcription Factor / metabolism
Oximes / pharmacology
Piperazines / pharmacology
Prognosis
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins / antagonists & inhibitors
Proto-Oncogene Proteins / genetics*
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins B-raf / antagonists & inhibitors
Proto-Oncogene Proteins B-raf / genetics
Proto-Oncogene Proteins B-raf / metabolism
Pyridones / pharmacology
Pyrimidines / pharmacology
Pyrimidinones / pharmacology
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
Receptor Protein-Tyrosine Kinases / genetics*
Receptor Protein-Tyrosine Kinases / metabolism
Signal Transduction
Skin Neoplasms / drug therapy*
Skin Neoplasms / genetics
Skin Neoplasms / metabolism
Skin Neoplasms / pathology
Sulfonamides / pharmacology
Vemurafenib
Xenograft Model Antitumor Assays

Substances

Aminopyridines
Antineoplastic Agents
Benzamides
Imidazoles
Indoles
MITF protein, human
Microphthalmia-Associated Transcription Factor
N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide
Oximes
Piperazines
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Pyridones
Pyrimidines
Pyrimidinones
Sulfonamides
Vemurafenib
trametinib
Imatinib Mesylate
Receptor Protein-Tyrosine Kinases
BRAF protein, human
Proto-Oncogene Proteins B-raf
Extracellular Signal-Regulated MAP Kinases
dabrafenib
Axl Receptor Tyrosine Kinase

Abstract

Publication types

MeSH terms

Substances

Grants and funding