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Cancer Discov DOI:10.1158/2159-8290.CD-13-0424

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

Publication TypeJournal Article
Year of Publication2014
AuthorsKonieczkowski, DJ, Johannessen, CM, Abudayyeh, O, Kim, JWook, Cooper, ZA, Piris, A, Frederick, DT, Barzily-Rokni, M, Straussman, R, Haq, R, Fisher, DE, Mesirov, JP, Hahn, WC, Flaherty, KT, Wargo, JA, Tamayo, P, Garraway, LA
JournalCancer Discov
Date Published2014 Jul
KeywordsAnilides, Benzimidazoles, Benzocycloheptenes, Cell Line, Tumor, Cells, Cultured, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Hepatocyte Growth Factor, Humans, Indoles, MAP Kinase Signaling System, Melanocytes, Melanoma, Microphthalmia-Associated Transcription Factor, NF-kappa B p50 Subunit, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-met, Pyridines, Quinolines, Sulfonamides, Triazoles

UNLABELLED: 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.


Alternate JournalCancer Discov
PubMed ID24771846
PubMed Central IDPMC4154497
Grant ListP30 CA016672 / CA / NCI NIH HHS / United States
P01 CA163222 / CA / NCI NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
DP2 OD002750 / OD / NIH HHS / United States
R01 AR043369 / AR / NIAMS NIH HHS / United States
R01 CA154480 / CA / NCI NIH HHS / United States
T32GM007753 / GM / NIGMS NIH HHS / United States
R01 CA121941 / CA / NCI NIH HHS / United States
P50 CA127003 / CA / NCI NIH HHS / United States