Melanocyte-specific survival signaling confers drug resistance in BRAF-mutant melanoma.

  • Major finding: Melanocyte-specific survival signaling confers drug resistance in BRAF-mutant melanoma.

  • Concept: GPCR-mediated cAMP signaling network genes were identified in a gain-of-function resistance screen.

  • Impact: Suppression of melanocytic signaling may prolong responses to MAPK pathway inhibitors.

Single-agent or combined use of RAF or MEK inhibitors has significant clinical activity in patients with BRAF-mutant melanoma, but the long-term effectiveness of these agents is limited by the emergence of acquired resistance. To systematically characterize potential resistance mechanisms to MAPK pathway inhibitors, Johannessen and colleagues screened over 15,000 open reading frames in BRAF-mutant melanoma cells for those that conferred resistance to RAF, MEK, or ERK inhibitors or combined RAF and MEK inhibition. In total, 110 genes reduced drug sensitivity in at least two cell lines, with many imparting resistance to both single-agent and combination therapy. Notably, multiple genes identified were components of a G protein-coupled receptor (GPCR)-mediated cyclic AMP (cAMP)-dependent signaling network known to be critical for primary melanocyte growth, suggesting that activation of lineage-specific survival pathways may underlie resistance to MAPK pathway inhibition. Indeed, cAMP conferred resistance to all inhibitors tested and increased phosphorylation of CREB1 and ATF1, transcription factors that regulate expression of genes with cAMP response elements (CRE). CREs were identified in the promoters of 19 resistance genes (17%), including melanocyte lineage-specific transcription factor genes such as MITF, which is also a known melanoma oncogene. MITF was upregulated in a cAMP-dependent manner, and its knockdown or suppression by histone deacetylase inhibition reversed cAMP-dependent MAPK inhibitor resistance. In patient biopsy samples, CREB1 and ATF1 phosphorylation were initially suppressed upon RAF or RAF–MEK inhibitor treatment but increased to pretreatment levels in patients who relapsed. MITF levels also decreased upon initiation of MAPK inhibitor treatment and were partially restored in one patient who relapsed. Together, these findings are consistent with a model in which cAMP-dependent activation of lineage-specific transcription factors mediates resistance to MAPK inhibition in melanoma and suggest that targeting this lineage dependency may lead to more durable responses in some patients treated with MAPK inhibitors.

Johannessen CM, Johnson LA, Piccioni F, Townes A, Frederick DT, Donahue MK, et al. A melanocyte lineage program confers resistance to MAP kinase inhibition. Nature 2013 Nov 3 [Epub ahead of print].

©2013 American Association for Cancer Research.
2013