Profiling the transcriptional and translational response to BRAF targeted therapy in melanoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA791750 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17317869.fastq.gz | Fastqsanger.gz | |||
| SRR17317870.fastq.gz | Fastqsanger.gz | |||
| SRR17317871.fastq.gz | Fastqsanger.gz | |||
| SRR17317872.fastq.gz | Fastqsanger.gz | |||
| SRR17317873.fastq.gz | Fastqsanger.gz |
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Project description:Melanoma is an aggressive skin cancer with increasing incidence worldwide. The development of BRAF kinase inhibitors as targeted treatments for patients with BRAF-mutant tumours contributed profoundly to an improved overall survival of patients with metastatic melanoma. Despite these promising results, the emergence of rapid resistance to targeted therapy remains a serious clinical issue. To investigate the impact of BRAF inhibitors on miRNomes and transcriptomes, we used in vitro melanoma models consisting of BRAF inhibitor-sensitive and -resistant cell lines generated in our laboratory. miRNA and gene expression were assessed by microarray analyses of the BRAF inhibitor sensitive melanoma cells A375, IGR37, and 501Mel, as well as on the vemurafenib (PLX4032) - resistant cells A375_XP, IGR37_XP, 501Mel_XP, and dabrafenib (GSK2118436) - resistant cells A375_GP, IGR37_GP, 501Mel_GP. For each cell line the microarray experiment was performed in duplicates.
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Project description:Disrupting ATF4 expression mechanisms provides an effective strategy for BRAF-targeted melanoma therapy
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Project description:BRAF V600 mutation influences cellular signaling pathways for melanoma development. Here, we show that mutated BRAF plays an essential role in the adaptive stress response following activation of general control non-derepressible 2 (GCN2) kinase. In parallel with GCN2, BRAF ensures ATF4 induction by utilizing mTOR and eIF4B as downstream regulators during nutrient stress and BRAF-targeted, therapeutic stress. Upon pharmacological BRAF inhibition, this signaling pathway exhibits temporal resistance, compared with the MEK-ERK pathway, thereby enabling transient induction of ATF4 under GCN2 activation. Notably, the prevention of GCN2 activation, using a chemical inhibitor that we identified, produces synergistic cell killing with BRAF inhibition. Thus, oncogenic BRAF can collaborate with the GCN2–ATF4 pathway, promoting stress adaptation for cell survival.
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Project description:Melanoma cells are highly plastic and have the ability to switch to a dedifferentiated, invasive phenotype in response to multiple stimuli. Here, we show that exposure of melanoma cell lines and patient specimens to multiple stresses including BRAF-MEK inhibitor therapy, hypoxia and UV-irradiation leads to an increase in histone deacetylase 8 (HDAC8) expression/activity, and in turn, the adoption of a drug-resistant, invasive phenotype. Systems level analyses using mass spectrometry-based phosphoproteomics implicated HDAC8 in the regulation of MAPK and AP-1 signaling pathways. Introduction of HDAC8 into drug-naïve melanoma cells conveyed resistance both in vitro and in in vivo xenograft models. HDAC8-mediated BRAF inhibitor resistance was mediated via receptor tyrosine kinase (RTK) activation leading to Ras/CRAF/MEK/ERK signaling. Although HDACs primarily function at the histone level, they also regulate signaling through the modulation of non-histone substrates. In line with this, HDAC8 introduction decreased the acetylation of c-Jun, increasing its transcriptional activity and enriching for an AP-1 gene signature. Mutation of the putative c-Jun acetylation site at lysine residue 273 reduced the transcriptional activation of c-Jun in melanoma cells and conveyed resistance to BRAF inhibition through increased RTK expression and enhanced MAPK pathway activity. In vivo xenograft studies confirmed the key role of HDAC8 in therapeutic adaptation, with both non-selective and HDAC8-specific inhibitors enhancing the durability of response to BRAF inhibitor therapy. Our studies demonstrate that HDAC8-specific inhibitors could represent an excellent strategy to limit the adaptation of melanoma cells to multiple stresses and therapeutic interventions, including BRAF-MEK inhibitor combinations.
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