Low MITF/AXL Ratio Predicts Early Resistance to Multiple Targeted Drugs in Melanoma

Overview

Journal Nat Commun

Specialty Biology

Date 2014 Dec 16

PMID 25502142

Citations 346

Authors

Judith Muller

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

Affiliations

Soon will be listed here.

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.

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