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CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation

ABSTRACT: CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation

PROVIDER: PRJNA1104626 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28807033.fastq.gz	Fastqsanger.gz
	SRR28807034.fastq.gz	Fastqsanger.gz
	SRR28807035.fastq.gz	Fastqsanger.gz
	SRR28807036.fastq.gz	Fastqsanger.gz
	SRR28807037.fastq.gz	Fastqsanger.gz

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CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation

Project description:Neuroendocrine (NE) transformation is a mechanism of resistance to targeted therapy in lung and prostate adenocarcinomas leading to poor prognosis. Upregulation of the cell cycle kinase CDC7 occurred in tumors undergoing NE transformation, after TP53/RB1 co-inactivation, leading to induced sensitivity to the CDC7 inhibitor simurosertib. CDC7 inhibition suppressed NE transdifferentiation and extended response to targeted therapy in in vivo models of NE transformation by inducing the proteasome-mediated degradation of MYC, implicated in stemness and histological transformation. Ectopic overexpression of a degradation-resistant MYC isoform reestablished the NE transformation phenotype observed on targeted therapy, even in the presence of simurosertib. CDC7 inhibition also markedly extended response to standard cytotoxics in lung and prostate small cell carcinoma models. These results nominate CDC7 inhibition as a strategy to constrain lineage plasticity and to effectively treat NE tumors. As simurosertib clinical efficacy trials are ongoing, this concept could be readily translated for patients at risk.

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CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation I

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CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation

Project description:CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation

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CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation III

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CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation I

Project description:CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation I

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CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation II

Project description:CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation II

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CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation.

Project description:Neuroendocrine (NE) transformation is a mechanism of resistance to targeted therapy in lung and prostate adenocarcinomas leading to poor prognosis. Up to date, even if patients at high risk of transformation can be identified by the occurrence of Tumor Protein P53 (TP53) and Retinoblastoma Transcriptional Corepressor 1 (RB1) mutations in their tumors, no therapeutic strategies are available to prevent or delay histological transformation. Upregulation of the cell cycle kinase Cell Division Cycle 7 (CDC7) occurred in tumors during the initial steps of NE transformation, already after TP53/RB1 co-inactivation, leading to induced sensitivity to the CDC7 inhibitor simurosertib. CDC7 inhibition suppressed NE transdifferentiation and extended response to targeted therapy in in vivo models of NE transformation by inducing the proteasome-mediated degradation of the MYC Proto-Oncogen (MYC), implicated in stemness and histological transformation. Ectopic overexpression of a degradation-resistant MYC isoform reestablished the NE transformation phenotype observed on targeted therapy, even in the presence of simurosertib. CDC7 inhibition also markedly extended response to standard cytotoxics (cisplatin, irinotecan) in lung and prostate small cell carcinoma models. These results nominate CDC7 inhibition as a therapeutic strategy to constrain lineage plasticity, as well as to effectively treat NE tumors de novo or after transformation. As simurosertib clinical efficacy trials are ongoing, this concept could be readily translated for patients at risk of transformation.

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CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-05-01 | GSE252569 | GEO