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

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 r...

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Bibliographic Details
Published in:	Nature communications Vol. 5; no. 1; p. 5712
Main Authors:	Müller, Judith, Krijgsman, Oscar, Tsoi, Jennifer, Robert, Lidia, Hugo, Willy, Song, Chunying, Kong, Xiangju, Possik, Patricia A., Cornelissen-Steijger, Paulien D. M., Foppen, Marnix H Geukes, Kemper, Kristel, Goding, Colin R., McDermott, Ultan, Blank, Christian, Haanen, John, Graeber, Thomas G., Ribas, Antoni, Lo, Roger S., Peeper, Daniel S.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 15.12.2014 Nature Publishing Group
Subjects:	13 38 631/154/53/2423 631/67/1059/2326 631/67/1813/1634 82 96 Aminopyridines - pharmacology Animals Antineoplastic Agents - pharmacology 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 Humanities and Social Sciences Humans Imatinib Mesylate Imidazoles - pharmacology Indoles - pharmacology Melanoma Melanoma - drug therapy Melanoma - genetics Melanoma - metabolism Melanoma - pathology Mice Microphthalmia-Associated Transcription Factor - genetics Microphthalmia-Associated Transcription Factor - metabolism multidisciplinary 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 Science Science (multidisciplinary) Signal Transduction Skin Neoplasms - drug therapy Skin Neoplasms - genetics Skin Neoplasms - metabolism Skin Neoplasms - pathology Sulfonamides - pharmacology Xenograft Model Antitumor Assays
ISSN:	2041-1723, 2041-1723
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Summary:	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. Increased expression of MITF transcription factor is thought to promote melanoma progression and kinase inhibitor resistance. Here Muller et al . show that MITF loss is also common in melanomas and confers kinase inhibitor resistance due to upregulation of AXL and other receptor tyrosine kinases.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 content type line 14 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/ncomms6712