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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.

Original publication

DOI

10.1038/ncomms6712

Type

Journal article

Journal

Nature communications

Publication Date

15/12/2014

Volume

5

Pages

5712 - 5712

Addresses

Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.

Keywords

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