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Targeting the unwindosome by mebendazole is a vulnerability of chemoresistant hepatoblastoma

ABSTRACT: Targeting the unwindosome by mebendazole is a vulnerability of chemoresistant hepatoblastoma

PROVIDER: PRJNA862538 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR20653231_1.fastq.gz	Fastqsanger.gz
	SRR20653231_2.fastq.gz	Fastqsanger.gz
	SRR20653232_1.fastq.gz	Fastqsanger.gz
	SRR20653232_2.fastq.gz	Fastqsanger.gz
	SRR20653233_1.fastq.gz	Fastqsanger.gz

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Targeting the unwindosome by mebendazole is a vulnerability of chemoresistant hepatoblastoma

Project description:We identified mebendazole as a drug to circumvent chemoresistance in hepatoblastoma cell lines that are resistant to cisplatin. In order to identify the mechanistic basis of mebendazole function, we performed gene expression analysis of three mebendazole-treated hepatoblastoma cell lines.

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Targeting the Unwindosome by Mebendazole Is a Vulnerability of Chemoresistant Hepatoblastoma.

Project description:Resistance to conventional chemotherapy remains a huge challenge in the clinical management of hepatoblastoma, the most common liver tumor in childhood. By integrating the gene expression data of hepatoblastoma patients into the perturbation prediction tool Connectivity Map, we identified the clinical widely used anthelmintic mebendazole as a drug to circumvent chemoresistance in permanent and patient-derived xenograft cell lines that are resistant to cisplatin, the therapeutic backbone of hepatoblastoma treatment. Viability assays clearly indicated a potent reduction of tumor cell growth upon mebendazole treatment in a dose-dependent manner. The combination of mebendazole and cisplatin revealed a strong synergistic effect, which was comparable to the one seen with cisplatin and doxorubicin, the current treatment for high-risk hepatoblastoma patients. Moreover, mebendazole treatment resulted in reduced colony and tumor spheroid formation capabilities, cell cycle arrest, and induction of apoptosis of hepatoblastoma cells. Mechanistically, mebendazole causes blockage of microtubule formation and transcriptional downregulation of genes encoding the unwindosome, which are highly expressed in chemoresistant tumors. Most importantly, mebendazole significantly reduced tumor growth in a subcutaneous xenograft transplantation mouse model without side effects. In conclusion, our results strongly support the clinical use of mebendazole in the treatment of chemoresistant hepatoblastoma and highlight the potential theranostic value of unwindosome-associated genes.

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Project description:Triple negative breast cancer (TNBC) accounts for 15-20% of breast cancer cases in the United States. Systemic neoadjuvant chemotherapy (NACT), with or without immunotherapy, is the current standard of care for patients with early-stage TNBC. However, up to 70% of TNBC patients have significant residual disease once NACT is completed, which is associated with a high risk of developing recurrence within two to three years of surgical resection. To identify targetable vulnerabilities in chemoresistant TNBC, we generated longitudinal patient-derived xenograft (PDX) models from TNBC tumors before and after patients received NACT. We then compiled transcriptomes and drug response profiles for all models. Transcriptomic analysis identified the enrichment of aberrant protein homeostasis pathways in models from post-NACT tumors relative to pre-NACT tumors. This observation correlated with increased sensitivity in vitro to inhibitors targeting the proteasome, heat shock proteins, and neddylation pathways. Pevonedistat, a drug annotated as a NEDD8-activating enzyme (NAE) inhibitor, was prioritized for validation in vivo and demonstrated efficacy as a single agent in multiple PDX models of TNBC. Pharmacotranscriptomic analysis identified a pathway-level correlation between pevonedistat activity and post-translational modification (PTM) machinery, particularly involving neddylation and sumoylation targets. Elevated levels of both NEDD8 and SUMO1 were observed in models exhibiting a favorable response to pevonedistat compared to those with a less favorable response in vivo. Moreover, a correlation emerged between the expression of neddylation-regulated pathways and tumor response to pevonedistat, indicating that targeting these PTM pathways may prove effective in combating chemoresistant TNBC.

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