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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:Nearly 50% of cutaneous melanomas carry activating mutations on the BRAF oncogene, and the combination of BRAF- and MEK-inhibitors (BRAF/MEKi) is frequently used for their clinical management. One major drawback of BRAF/MEKi targeted therapy is the rapid development of therapeutic resistance, which can occur via multiple mechanisms, including the metabolic rewiring of cancer cells that often involves the upregulation of mitochondrial bionergetics and NAD+ biosynthetic pathways. mTORC2 is a signaling complex that requires the presence of its essential RICTOR subunit to play its regulatory functions in cell growth and metabolism. mTORC2 is believed to play mostly pro-oncogenic roles in several tumor types, including melanoma. However, bioinformatics analysis of TCGA melanoma patients’ database revealed that low RICTOR levels in tumors correlate with an overall worse clinical outcome. GSEA analysis of low-RICTOR tumors evidenced also a gene expression signature suggestive of activation of mitochondrial energy producing pathways. On these bases, we have hypothesized that inhibition of mTORC2 activity may render BRAFV600E melanoma cells resistant to BRAFi/MEKi. We show here that RICTOR/mTORC2-deficient cells are intrinsically tolerant to BRAFi/MEKi, and anticipate the onset of resistance to BRAFi after sustained drug exposure both in vitro and in vivo, indicating that mTORC2 activity normally opposes the acquisition of targeted therapy resistance in BRAFV600E melanomas. Mechanistically, RICTOR-deficient cells show an enhanced mitochondrial respiratory potential and increased expression of nicotinamide phosphoribosyltransferase (NAMPT) protein, the rate-limiting enzyme of NAD+ salvage pathway, and pharmacological inhibition of these processes in RICTOR-deficient cells is sufficient to restore sensitivity to BRAFi. Thus, our work identifies a novel role for mTORC2 in favoring the responses of BRAF-mutated melanoma cells to targeted therapy, and suggest that the evaluation of the intratumor level of RICTOR may help to predict the responses of melanoma patients to these treatments.

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

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