A melanocyte lineage program confers resistance to MAP kinase pathway inhibition.
Johannessen, Cory M. 1,2,3; Johnson, Laura A. 1,2,+; Piccioni, Federica 1; Townes, Aisha 1; Frederick, Dennie T. 4; Donahue, Melanie K. 1; Narayan, Rajiv 1; Flaherty, Keith T. 4; Wargo, Jennifer A. 4; Root, David E. 1; Garraway, Levi A. 1,2,3
[Letter]
Nature.
504(7478):138-142, December 5, 2013.
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: Malignant melanomas harbouring point mutations (Val600Glu) in the serine/threonine-protein kinase BRAF (BRAF(V600E)) depend on RAF-MEK-ERK signalling for tumour cell growth 1. RAF and MEK inhibitors show remarkable clinical efficacy in BRAF(V600E) melanoma 2,3; however, resistance to these agents remains a formidable challenge 2,4. Global characterization of resistance mechanisms may inform the development of more effective therapeutic combinations. Here we carried out systematic gain-of-function resistance studies by expressing more than 15,500 genes individually in a BRAF(V600E) melanoma cell line treated with RAF, MEK, ERK or combined RAF-MEK inhibitors. These studies revealed a cyclic-AMP-dependent melanocytic signalling 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 BRAF(V600E) melanoma patients revealed that phosphorylated (active) CREB was suppressed by RAF-MEK inhibition but restored in relapsing tumours. 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 MAPK-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 signalling- and chromatin-directed therapeutics.
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