A melanocyte lineage program confers resistance to MAP kinase pathway inhibition.

Nature
Authors
Keywords
Abstract

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. RAF and MEK inhibitors show remarkable clinical efficacy in BRAF(V600E) melanoma; however, resistance to these agents remains a formidable challenge. 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.

Year of Publication
2013
Journal
Nature
Volume
504
Issue
7478
Pages
138-42
Date Published
2013 Dec 05
ISSN
1476-4687
URL
DOI
10.1038/nature12688
PubMed ID
24185007
PubMed Central ID
PMC4098832
Links
Grant list
P01 CA163222 / CA / NCI NIH HHS / United States
P50 CA093683 / CA / NCI NIH HHS / United States
U54 HG006093 / HG / NHGRI NIH HHS / United States
DP2OD002750 / OD / NIH HHS / United States
DP2 OD002750 / OD / NIH HHS / United States
P50CA93683 / CA / NCI NIH HHS / United States
R33 CA155554 / CA / NCI NIH HHS / United States
U54 CA112962 / CA / NCI NIH HHS / United States
U01 HG006492 / HG / NHGRI NIH HHS / United States