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Cancer Discov. 2014 Jul;4(7):816-27. doi: 10.1158/2159-8290.CD-13-0424. Epub 2014 Apr 25.

A melanoma cell state distinction influences sensitivity to MAPK pathway inhibitors.

Author information

1
Authors' Affiliations:Broad Institute of Harvard and MIT, Cambridge; Department of Medical Oncology, Dana-Farber Cancer Institute; Divisions of.
2
Authors' Affiliations:Broad Institute of Harvard and MIT, Cambridge;
3
Surgical Oncology, and Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
4
Dermatopathology and.
5
Surgical Oncology.
6
Massachusetts General Hospital Cancer Center, and Dermatology and Cutaneous Biology Research Center, Massachusetts General Hospital, Boston, Massachusetts; Departments of.
7
Massachusetts General Hospital Cancer Center, and.
8
Authors' Affiliations:Broad Institute of Harvard and MIT, Cambridge; Department of Medical Oncology, Dana-Farber Cancer Institute; Divisions of levi_garraway@dfci.harvard.edu.

Abstract

Most melanomas harbor oncogenic BRAF(V600) mutations, which constitutively activate the MAPK pathway. Although MAPK pathway inhibitors show clinical benefit in BRAF(V600)-mutant melanoma, it remains incompletely understood why 10% to 20% of patients fail to respond. Here, we show that RAF inhibitor-sensitive and inhibitor-resistant BRAF(V600)-mutant melanomas display distinct transcriptional profiles. Whereas most drug-sensitive cell lines and patient biopsies showed high expression and activity of the melanocytic lineage transcription factor MITF, intrinsically resistant cell lines and biopsies displayed low MITF expression but higher levels of NF-κB signaling and the receptor tyrosine kinase AXL. In vitro, these MITF-low/NF-κB-high melanomas were resistant to inhibition of RAF and MEK, singly or in combination, and ERK. Moreover, in cell lines, NF-κB activation antagonized MITF expression and induced both resistance marker genes and drug resistance. Thus, distinct cell states characterized by MITF or NF-κB activity may influence intrinsic resistance to MAPK pathway inhibitors in BRAF(V600)-mutant melanoma.

SIGNIFICANCE:

Although most BRAF(V600)-mutant melanomas are sensitive to RAF and/or MEK inhibitors, a subset fails to respond to such treatment. This study characterizes a transcriptional cell state distinction linked to MITF and NF-κB that may modulate intrinsic sensitivity of melanomas to MAPK pathway inhibitors.

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PMID:
24771846
PMCID:
PMC4154497
DOI:
10.1158/2159-8290.CD-13-0424
[Indexed for MEDLINE]
Free PMC Article

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