dc.contributor.author | Johannessen, Cory M. | en_US |
dc.contributor.author | Johnson, Laura A. | en_US |
dc.contributor.author | Piccioni, Federica | en_US |
dc.contributor.author | Townes, Aisha | en_US |
dc.contributor.author | Frederick, Dennie T. | en_US |
dc.contributor.author | Donahue, Melanie K. | en_US |
dc.contributor.author | Narayan, Rajiv | en_US |
dc.contributor.author | Flaherty, Keith T. | en_US |
dc.contributor.author | Wargo, Jennifer A. | en_US |
dc.contributor.author | Root, David E. | en_US |
dc.contributor.author | Garraway, Levi A. | en_US |
dc.date.accessioned | 2014-08-13T13:59:43Z | |
dc.date.issued | 2014 | en_US |
dc.identifier.citation | Johannessen, C. M., L. A. Johnson, F. Piccioni, A. Townes, D. T. Frederick, M. K. Donahue, R. Narayan, et al. 2014. “A melanocyte lineage program confers resistance to MAP kinase pathway inhibition.” Nature 504 (7478): 138-142. doi:10.1038/nature12688. http://dx.doi.org/10.1038/nature12688. | en |
dc.identifier.issn | 0028-0836 | en |
dc.identifier.uri | http://nrs.harvard.edu/urn-3:HUL.InstRepos:12717516 | |
dc.description.abstract | BRAFV600E-mutant malignant melanomas depend on RAF/MEK/ERK (MAPK) signaling for tumor cell growth1. RAF and MEK inhibitors show remarkable clinical efficacy in BRAFV600E melanoma2, 3; however, resistance to these agents remains a formidable challenge2, 4. Global characterization of resistance mechanisms may inform the development of more effective therapeutic combinations. Here, we performed systematic gain-of-function resistance studies by expressing >15,500 genes individually in a BRAFV600E melanoma cell line treated with RAF, MEK, ERK, or combined RAF/MEK inhibitors. These studies revealed a cyclic AMP-dependent melanocytic signaling network not previously associated with drug resistance, including G-protein coupled receptors, adenyl cyclase, protein kinase A and cAMP response element binding protein (CREB). Preliminary analysis of biopsies from BRAFV600E melanoma patients revealed that phosphorylated (active) CREB was suppressed by RAF/MEK-inhibition but restored in relapsing tumors. Expression of transcription factors activated downstream of MAP kinase and cAMP pathways also conferred resistance, including c-FOS, NR4A1, NR4A2 and MITF. Combined treatment with MAP kinase pathway and histone deacetylase inhibitors suppressed MITF expression and cAMP-mediated resistance. Collectively, these data suggest that oncogenic dysregulation of a melanocyte lineage dependency can cause resistance to RAF/MEK/ERK inhibition, which may be overcome by combining signaling- and chromatin-directed therapeutics. | en |
dc.language.iso | en_US | en |
dc.relation.isversionof | doi:10.1038/nature12688 | en |
dc.relation.hasversion | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098832/pdf/ | en |
dash.license | LAA | en_US |
dc.title | A melanocyte lineage program confers resistance to MAP kinase pathway inhibition | en |
dc.type | Journal Article | en_US |
dc.description.version | Version of Record | en |
dc.relation.journal | Nature | en |
dash.depositing.author | Johannessen, Cory M. | en_US |
dc.date.available | 2014-08-13T13:59:43Z | |
dc.identifier.doi | 10.1038/nature12688 | * |
dash.authorsordered | false | |
dash.contributor.affiliated | Johannessen, Cory M. | |
dash.contributor.affiliated | Garraway, Levi | |
dash.contributor.affiliated | Wargo, Jennifer Ann | |
dash.contributor.affiliated | Flaherty, Keith | |