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RNASeq analysis of NB1691 neuroblastoma cells treated with MDM2-p53 inhibitor RG7388 alone and in combination with temozolomide

ABSTRACT: RNASeq analysis of NB1691 neuroblastoma cells treated with MDM2-p53 inhibitor RG7388 alone and in combination with temozolomide

PROVIDER: PRJNA414128 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6166440_1.fastq.gz	Fastqsanger.gz
	SRR6166440_2.fastq.gz	Fastqsanger.gz
	SRR6166450_1.fastq.gz	Fastqsanger.gz
	SRR6166450_2.fastq.gz	Fastqsanger.gz
	SRR6166431_1.fastq.gz	Fastqsanger.gz

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RNASeq analysis of NB1691 neuroblastoma cells treated with MDM2-p53 inhibitor RG7388 alone and in combination with temozolomide

Project description:To further identify potential mechanisms involved in combining RG7388 with temozolomide, GSEA was performed and revealed that RG7388 and temozolomide act cooperatively to upregulate the p53 pathway and downregulate MYC targets, the former resulting in significantly greater induction of several apoptotic genes.

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Pre-clinical evaluation of the MDM2-p53 antagonist RG7388 alone and in combination with chemotherapy in neuroblastoma.

Project description:Neuroblastoma is a predominantly p53 wild-type (wt) tumour and MDM2-p53 antagonists offer a novel therapeutic strategy for neuroblastoma patients. RG7388 (Roche) is currently undergoing early phase clinical evaluation in adults. This study assessed the efficacy of RG7388 as a single-agent and in combination with chemotherapies currently used to treat neuroblastoma in a panel of neuroblastoma cell lines. RG7388 GI50 concentrations were determined in 21 p53-wt and mutant neuroblastoma cell lines of varying MYCN, MDM2 and p14(ARF) status, together with MYCN-regulatable Tet21N cells. The primary determinant of response was the presence of wt p53, and overall there was a >200-fold difference in RG7388 GI50 concentrations for p53-wt versus mutant cell lines. Tet21N MYCN+ cells were significantly more sensitive to RG7388 compared with MYCN- cells. Using median-effect analysis in 5 p53-wt neuroblastoma cell lines, selected combinations of RG7388 with cisplatin, doxorubicin, topotecan, temozolomide and busulfan were synergistic. Furthermore, combination treatments led to increased apoptosis, as evident by higher caspase-3/7 activity compared to either agent alone. These data show that RG7388 is highly potent against p53-wt neuroblastoma cells, and strongly supports its further evaluation as a novel therapy for patients with high-risk neuroblastoma and wt p53 to potentially improve survival and/or reduce toxicity.

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