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 and Daniel S. Peeper ()
Additional contact information
Judith Müller: The Netherlands Cancer Institute
Oscar Krijgsman: The Netherlands Cancer Institute
Jennifer Tsoi: David Geffen School of Medicine at University of California, University of California, Los Angeles (UCLA)
Lidia Robert: David Geffen School of Medicine at University of California, Los Angeles (UCLA)
Willy Hugo: David Geffen School of Medicine at University of California, Los Angeles (UCLA)
Chunying Song: David Geffen School of Medicine at University of California, Los Angeles (UCLA)
Xiangju Kong: David Geffen School of Medicine at University of California, Los Angeles (UCLA)
Patricia A. Possik: The Netherlands Cancer Institute
Paulien D. M. Cornelissen-Steijger: The Netherlands Cancer Institute
Marnix H Geukes Foppen: The Netherlands Cancer Institute
Kristel Kemper: The Netherlands Cancer Institute
Colin R. Goding: Ludwig Institute for Cancer Research, University of Oxford
Ultan McDermott: Wellcome Trust Sanger Institute, Genome Campus
Christian Blank: The Netherlands Cancer Institute
John Haanen: The Netherlands Cancer Institute
Thomas G. Graeber: David Geffen School of Medicine at University of California, University of California, Los Angeles (UCLA)
Antoni Ribas: David Geffen School of Medicine at University of California, University of California, Los Angeles (UCLA)
Roger S. Lo: David Geffen School of Medicine at University of California, University of California, Los Angeles (UCLA)
Daniel S. Peeper: The Netherlands Cancer Institute

Nature Communications, 2014, vol. 5, issue 1, 1-15

Abstract: 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.

Date: 2014
References: Add references at CitEc
Citations: View citations in EconPapers (5)

Downloads: (external link)
https://www.nature.com/articles/ncomms6712 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6712

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms6712

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().