@article{b9af0e5199924fc68d3d9ea67c4ea6cf,
title = "A melanoma cell state distinction influences sensitivity to MAPK pathway inhibitors",
abstract = "Most melanomas harbor oncogenic BRAFV600 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 BRAFV600 -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.",
author = "Konieczkowski, {David J.} and Johannessen, {Cory M.} and Omar Abudayyeh and Kim, {Jong Wook} and Cooper, {Zachary A.} and Adriano Piris and Frederick, {Dennie T.} and Michal Barzily-Rokni and Ravid Straussman and Rizwan Haq and Fisher, {David E.} and Mesirov, {Jill P.} and Hahn, {William C.} and Flaherty, {Keith T.} and Wargo, {Jennifer A.} and Pablo Tamayo and Garraway, {Levi A.}",
note = "D.J. Konieczkowski was supported by training grant T32GM007753 from the National Institute of General Medical Sciences. L.A. Garraway was supported by grants from the NIH, NCI, Melanoma Research Alliance, Starr Cancer Consortium, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. W.C. Hahn has received a commercial research grant from Novartis and is a consultant/advisory board member of the same. J.A. Wargo has received honoraria from the Speakers Bureau of Dava Oncology. L.A. Garraway has received a commercial research grant from Novartis, has ownership interest (including patents) in Foundation Medicine, and is a consultant/advisory board member of Millennium, Novartis, and Boehringer Ingelheim. No potential conflicts of interest were disclosed by the other authors. Authors' Contributions Conception and design: D.J. Konieczkowski, C.M. Johannessen, R. Haq, L.A. Garraway Development of methodology: D.J. Konieczkowski, O. Abudayyeh, M. Barzily-Rokni, J.P. Mesirov, W.C. Hahn, L.A. Garraway Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): D.J. Konieczkowski, C.M. Johannessen, J.W. Kim, Z.A. Cooper, A. Piris, D.T. Frederick, R. Straussman, J.A. Wargo Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): D.J. Konieczkowski, C.M. Johannessen, O. Abudayyeh, Z.A. Cooper, A. Piris, J.P. Mesirov, K.T. Flaherty, J.A. Wargo, P. Tamayo, L.A. Garraway Writing, review, and/or revision of the manuscript: D.J. Konieczkowski, C.M. Johannessen, O. Abudayyeh, J.W. Kim, A. Piris, D.T. Frederick, W.C. Hahn, K.T. Flaherty, J.A. Wargo, L.A. Garraway Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): C.M. Johannessen, D.T. Frederick Study supervision: C.M. Johannessen, L.A. Garraway Creation of BRAF inhibitor cultured-to-resistant melanoma cell lines: R. Straussman Contribution of key materials: D.E. Fisher",
year = "2014",
month = jul,
doi = "https://doi.org/10.1158/2159-8290.CD-13-0424",
language = "الإنجليزيّة",
volume = "4",
pages = "816--827",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "John Wiley and Sons Inc.",
number = "7",
}