A Melanocyte Lineage Program Confers Resistance to MAP Kinase Pathway Inhibition

Nature. 2013 Dec 5;504(7478):138-42. doi: 10.1038/nature12688. Epub 2013 Nov 3.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Melanocytes / drug effects*
  • Melanocytes / enzymology
  • Melanoma / enzymology
  • Melanoma / physiopathology
  • Mitogen-Activated Protein Kinases / metabolism*
  • Protein Kinase Inhibitors / pharmacology*
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Transcription Factors
  • Cyclic AMP
  • CREB-Binding Protein
  • Mitogen-Activated Protein Kinases