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Expression data for melanoma cell lines with different resistance to SBI-0640756

ABSTRACT: The emergence of effective inhibitors for BRAF-mutant melanoma has had major impact on clinical management of melanoma 1,2. The initial success of such treatments, however, has been limited due to the propensity of melanomas to develop resistance 3-5. In most cases, mechanisms underlying BRAFi-resistance include activation of genetic or epigenetic pathways that circumvent targeted BRAF and restore MAPK and related signaling to levels sufficient to encourage tumorigenesis 3-7. This outcome has led to development of combination therapies targeting both BRAF and associated pathways, such as MEK and PI3K 8,9, albeit, with limited success. Furthermore, 50% of melanomas, such as those harboring NRAS and NF1 mutations, lack BRAF mutations and are thus not amenable to BRAFi therapy 10,11. Thus tumor chemoresistance and the lack of therapies for BRAF wild-type (WT) tumors remains a major clinical challenge. Disrupting the eukaryotic translation initiation factor 4F (eIF4F) complex has been an appealing strategy to potentiate effectiveness of existing cancer therapies. We identify that the small molecule SBI-0640756 (SBI-756) binds to eIF4G1 and dissociates it from eIF4E, leading to disruption of the eIF4F complex. SBI-756 treatment also inhibited AKT, NF-κB and mTOR signaling. We detected the melanoma cell lines have different response to SBI-756. It important to invertigate genes and pathways in melanoma cells resistant to SBI-756.

ORGANISM(S): Homo sapiens

PROVIDER: GSE66401 | GEO | 2016/05/01

SECONDARY ACCESSION(S): PRJNA276757

REPOSITORIES: GEO

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Project description:BRAF oncogene is mutated in ~50% of human cutaneous melanomas. The BRAF V600E mutation leads to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway fuelling cancer growth. The inhibitors of BRAF V600E (BRAFi), lead to massive and high response rate. However, BRAFi-resistant cells that operate as a cellular reservoir for relapses severely limits the duration of the clinical response. The recent depiction of these resistant cells did not identify druggable targets to ensure long-term survival under BRAFi. Here, we identify the aryl hydrocarbon receptor (AhR) as a target to eradicate resistant cells. We show that BRAFi bind to AhR on a new site, named beta-pocket, and reprogram gene expression independently of its partner ARNT. beta-pocket activation induces a pigmentation signature, which is associated to BRAFi-induced cell death of sensitive BRAF V600E melanoma cells and tumour shrinkage. Intriguingly, in resistant cells, BRAFi does not induced a pigmentation signature since these cells display another AhR program; AhR-ARNT dependant. By this way, AhR directs several key BRAFi-resistant genes. At single cell level, this constitutive activation of AhR-ARNT is identified in rare cells before BRAFi-treatment of melanoma tumours and an enrichment of these alpha-cells is observed under BRAFi. Our data strongly suggest that an endogenous AhR ligand activates AhR-ARNT via the canonical AhR pocket (alpha-pocket), thus favouring BRAFi-resistant gene expression. Importantly, we identify the clinically compatible AhR antagonist, the resveratrol (RSV), able to abrogate the deleterious constitutive activation of AhR and to reduce the cellular reservoir for the relapse. Taken together, this work reveals that constitutive AhR signalling drives BRAFi resistance and constitutes a therapeutic target to achieve long-term patient survival under BRAFi. More broadly, the constitutive activation of AhR by endogenous ligands is in line with the ability of UV radiations to generate potent AhR ligands and to favour melanoma onset.

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Expression data for melanoma cell lines with different resistance to SBI-0640756

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