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Protein neddylation as a therapeutic target in pulomonary and extrapulonary small cell carcinomas

ABSTRACT: Protein neddylation as a therapeutic target in pulomonary and extrapulonary small cell carcinomas

PROVIDER: PRJNA718864 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14119300.fastq.gz	Fastqsanger.gz
	SRR14119301.fastq.gz	Fastqsanger.gz
	SRR14119302.fastq.gz	Fastqsanger.gz
	SRR14119409.fastq.gz	Fastqsanger.gz
	SRR14119410.fastq.gz	Fastqsanger.gz

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Protein neddylation as a therapeutic target in pulmonary and extrapulmonary small cell carcinomas.

Project description:Small cell lung carcinoma (SCLC) is among the most lethal of all solid tumor malignancies. In an effort to identify novel therapeutic approaches for this recalcitrant cancer type, we applied genome-scale CRISPR/Cas9 inactivation screens to cell lines that we derived from a murine model of SCLC. SCLC cells were particularly sensitive to the deletion of NEDD8 and other neddylation pathway genes. Genetic suppression or pharmacological inhibition of this pathway using MLN4924 caused cell death not only in mouse SCLC cell lines but also in patient-derived xenograft (PDX) models of pulmonary and extrapulmonary small cell carcinoma treated ex vivo or in vivo. A subset of PDX models were exceptionally sensitive to neddylation inhibition. Neddylation inhibition suppressed expression of major regulators of neuroendocrine cell state such as INSM1 and ASCL1, which a subset of SCLC rely upon for cell proliferation and survival. To identify potential mechanisms of resistance to neddylation inhibition, we performed a genome-scale CRISPR/Cas9 suppressor screen. Deletion of components of the COP9 signalosome strongly mitigated the effects of neddylation inhibition in small cell carcinoma, including the ability of MLN4924 to suppress neuroendocrine transcriptional program expression. This work identifies neddylation as a regulator of neuroendocrine cell state and potential therapeutic target for small cell carcinomas.

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Organoid-based drug screening reveals neddylation as therapeutic target for malignant rhabdoid tumors

Project description:Malignant rhabdoid tumors (MRT) represent one of the most aggressive childhood malignancies. No effective treatment options are available, and prognosis is therefore dismal. Previous studies have demonstrated that tumor organoids capture the heterogeneity of patient tumors and can be used to predict patient therapy response. Here, we perform drug screening on patient-derived normal and tumor organoids to identify MRT-specific therapeutic vulnerabilities. We identify neddylation inhibitor MLN4924 as a potential therapeutic agent. Mechanistically, we find increased neddylation in MRT organoids and tissues and show that MLN4924 induces a cytotoxic response via upregulation of the unfolded protein response. Lastly, we demonstrate in vivo efficacy in an MRT PDX mouse model, in which single agent MLN4924 treatment significantly extends survival. Our study demonstrates that organoids can be used to find drugs selectively targeting tumor cells while leaving healthy cells unharmed and proposes neddylation inhibition as therapeutic strategy in MRT.

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Organoid-based drug screening reveals neddylation as therapeutic target for malignant rhabdoid tumors

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