Unknown

Dataset Information

0

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


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.

SUBMITTER: Johannessen CM 

PROVIDER: S-EPMC4098832 | biostudies-other | 2013 Dec

REPOSITORIES: biostudies-other

altmetric image

Publications


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 resistan  ...[more]

Similar Datasets

| S-EPMC6410847 | biostudies-literature
| S-EPMC3058384 | biostudies-literature
2024-09-20 | GSE200899 | GEO
| S-EPMC3947296 | biostudies-literature
| S-EPMC3600451 | biostudies-literature
| S-EPMC6114982 | biostudies-literature
| S-EPMC6385389 | biostudies-literature
| S-EPMC3467423 | biostudies-literature
| S-EPMC3161418 | biostudies-literature
| S-EPMC6849413 | biostudies-literature