RESEARCH ARTICLE A Melanoma Cell State Distinction Infl uences Sensitivity to MAPK Pathway Inhibitors

ABSTRACT Most melanomas harbor oncogenic BRAF V600 mutations, which constitutively acti-vate the MAPK pathway. Although MAPK pathway inhibitors show clinical benefi t 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 melano-mas display distinct transcriptional profi les. 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 infl uence 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 inhibi-tors, 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 MAP