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


CONCLUSIONS
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.
Authors' Affiliations:Broad Institute of Harvard and MIT, Cambridge; Department of Medical Oncology, Dana-Farber Cancer Institute; Divisions of.
David J
DJ
Konieczkowski
Authors' Affiliations:Broad Institute of Harvard and MIT, Cambridge; Department of Medical Oncology, Dana-Farber Cancer Institute; Divisions of.
Cory M
CM
Johannessen
Authors' Affiliations:Broad Institute of Harvard and MIT, Cambridge;
Omar
O
Abudayyeh
Authors' Affiliations:Broad Institute of Harvard and MIT, Cambridge; Department of Medical Oncology, Dana-Farber Cancer Institute; Divisions of.
Jong Wook
JW
Kim
Surgical Oncology, and Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Zachary A
ZA
Cooper
Dermatopathology and.
Adriano
A
Piris
Surgical Oncology.
Dennie T
DT
Frederick
Authors' Affiliations:Broad Institute of Harvard and MIT, Cambridge;
Michal
M
Barzily-Rokni
Authors' Affiliations:Broad Institute of Harvard and MIT, Cambridge;
Ravid
R
Straussman
Massachusetts General Hospital Cancer Center, and Dermatology and Cutaneous Biology Research Center, Massachusetts General Hospital, Boston, Massachusetts; Departments of.
Rizwan
R
Haq
Massachusetts General Hospital Cancer Center, and Dermatology and Cutaneous Biology Research Center, Massachusetts General Hospital, Boston, Massachusetts; Departments of.
David E
DE
Fisher
Authors' Affiliations:Broad Institute of Harvard and MIT, Cambridge;
Jill P
JP
Mesirov
Authors' Affiliations:Broad Institute of Harvard and MIT, Cambridge; Department of Medical Oncology, Dana-Farber Cancer Institute; Divisions of.
William C
WC
Hahn
Massachusetts General Hospital Cancer Center, and.
Keith T
KT
Flaherty
Surgical Oncology, and Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jennifer A
JA
Wargo
Authors' Affiliations:Broad Institute of Harvard and MIT, Cambridge;
Pablo
P
Tamayo
Authors' Affiliations:Broad Institute of Harvard and MIT, Cambridge; Department of Medical Oncology, Dana-Farber Cancer Institute; Divisions of levi_garraway@dfci.harvard.edu.
Levi A
LA
Garraway
D000813:Anilides / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001567:Benzocycloheptenes / Q000494:pharmacology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
C517975:AZD 6244; D000813:Anilides; D001562:Benzimidazoles; D001567:Benzocycloheptenes; C544831:GSK 1363089; C066855:HGF protein, human; D007211:Indoles; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; C528407:PLX 4720; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011804:Quinolines; D013449:Sulfonamides; D014230:Triazoles; C548378:bemcentinib; C558660:cabozantinib; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf