Publication Date:
2013-11-05
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098832/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098832/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Johannessen, Cory M -- Johnson, Laura A -- Piccioni, Federica -- Townes, Aisha -- Frederick, Dennie T -- Donahue, Melanie K -- Narayan, Rajiv -- Flaherty, Keith T -- Wargo, Jennifer A -- Root, David E -- Garraway, Levi A -- DP2 OD002750/OD/NIH HHS/ -- DP2OD002750/OD/NIH HHS/ -- P01 CA163222/CA/NCI NIH HHS/ -- P50CA93683/CA/NCI NIH HHS/ -- R33 CA155554/CA/NCI NIH HHS/ -- U01 HG006492/HG/NHGRI NIH HHS/ -- U54 CA112962/CA/NCI NIH HHS/ -- U54 HG006093/HG/NHGRI NIH HHS/ -- England -- Nature. 2013 Dec 5;504(7478):138-42. doi: 10.1038/nature12688. Epub 2013 Nov 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] The Broad Institute of Harvard University and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA [3] Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24185007" target="_blank"〉PubMed〈/a〉
Keywords:
Antineoplastic Agents/*pharmacology
;
CREB-Binding Protein/metabolism
;
Cell Line, Tumor
;
Cell Lineage
;
Cyclic AMP/metabolism
;
Drug Resistance, Neoplasm/*genetics
;
Gene Expression Regulation, Neoplastic
;
HEK293 Cells
;
Humans
;
Melanocytes/cytology/*drug effects/enzymology
;
Melanoma/enzymology/physiopathology
;
Mitogen-Activated Protein Kinases/*metabolism
;
Protein Kinase Inhibitors/*pharmacology
;
Signal Transduction
;
Transcription Factors/genetics/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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