The DOI matches its Crossref record; 19 of the 19 references it cites were found in a registry or an index.
A Melanoma Cell State Distinction Influences Sensitivity to MAPK Pathway Inhibitors
Open accessAbstract
Most melanomas harbor oncogenic BRAFV600 mutations, which constitutively activate the MAPK pathway. Although MAPK pathway inhibitors show clinical benefit in BRAFV600-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 BRAFV600-mutant melanoma. Significance: Although most BRAFV600-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. Cancer Discov; 4(7); 816–27. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 745
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Metadata
- Authors
- Konieczkowski, D. J., Johannessen, C. M., Abudayyeh, O., Kim, J. W., Cooper, Z. A., Piris, A., Frederick, D. T., Barzily-Rokni, M., Straussman, R., Haq, R., Fisher, D. E., Mesirov, J. P., Hahn, W. C., Flaherty, K. T., Wargo, J. A., Tamayo, P., & Garraway, L. A.
- Venue
- Cancer Discovery
- Published
- 2014-07-01
- Volume
- 4
- Issue
- 7
- Pages
- 816-827
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- OpenAlex
- W2158416296
- Cited by
- 535
- References
- 19
- FWCI
- 18.13
- Type
- journal article
- Language
- en
- Open access
- green
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- Konieczkowski, D. J., Johannessen, C. M., Abudayyeh, O., Kim, J. W., Cooper, Z. A., Piris, A., Frederick, D. T., Barzily-Rokni, M., Straussman, R., Haq, R., Fisher, D. E., Mesirov, J. P., Hahn, W. C., Flaherty, K. T., Wargo, J. A., Tamayo, P., & Garraway, L. A. (2014). A Melanoma Cell State Distinction Influences Sensitivity to MAPK Pathway Inhibitors. Cancer Discovery. https://doi.org/10.1158/2159-8290.cd-13-0424
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