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Transcriptional Targeting Of Oncogene Addiction In Medullary Thyroid Cancer [RNA-Seq]

ABSTRACT: Transcriptional Targeting Of Oncogene Addiction In Medullary Thyroid Cancer [RNA-Seq]

PROVIDER: PRJNA464055 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7124060_1.fastq.gz	Fastqsanger.gz
	SRR7124060_2.fastq.gz	Fastqsanger.gz
	SRR7124061_1.fastq.gz	Fastqsanger.gz
	SRR7124061_2.fastq.gz	Fastqsanger.gz
	SRR7124062_1.fastq.gz	Fastqsanger.gz

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Transcriptional Targeting Of Oncogene Addiction In Medullary Thyroid Cancer

Project description:Transcriptional Targeting Of Oncogene Addiction In Medullary Thyroid Cancer

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Transcriptional Targeting Of Oncogene Addiction In Medullary Thyroid Cancer [ChIP-Seq]

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Transcriptional Targeting Of Oncogene Addiction In Medullary Thyroid Cancer [RNA-Seq]

Project description:Metastatic medullary thyroid cancer (MTC) is a currently incurable disease. FDA approved therapies that target RET, a commonly mutated receptor tyrosine kinase in MTC, and other receptor tyrosine kinases, do not result in complete responses and acquired resistance is universal due to “gatekeeper” mutation in Ret or overactivation of alternative signaling pathways. Based on data from human MTCs and a number of murine models, the CDK/RB cell cycle pathway is a potential alternative target for MTC. The objective of this study was to determine if CDKs represent therapeutic targets for MTC and to define mechanisms of activity. We demonstrate that targeting the CDK/RB pathway with Palbociclib (CDK4/6 inhibitor) is not cytotoxic to MTC cells but that Dinaciclib (CDK1/2/5/9 inhibitor) remarkably reduced cell viability and proliferation at low doses in two MTC cell lines accompanied by loss of CDK9 and RET protein and mRNA levels. In human tumors, CDK9 protein was highly expressed and array CGH demonstrated copy number gain in 11/30 analyzed tumors. RNA sequencing demonstrated that RNA polymerase II-dependent transcription was markedly reduced by Dinaciclib, consistent with transcriptional mode of action. Subsequent studies using the CDK7 inhibitor, THZ1, demonstrated high potency vs. the MTC cell lines and marked loss of RET mRNA and protein. In silico analysis, and CHIP-Sequencing using H3K27Ac antibody confirmed that RET is associated with a super-enhancer in RET-mutated MTC cells. In summary, this study reveals a novel mechanism of RET transcription regulation that represents a potentially translatable finding for new therapeutic approaches for RET-mutated MTC.

2018-12-25 | GSE114069 | GEO

Transcriptional Targeting Of Oncogene Addiction In Medullary Thyroid Cancer [ChIP-Seq]

2018-12-25 | GSE114068 | GEO

Transcriptional targeting of oncogene addiction in medullary thyroid cancer.

Project description:Metastatic medullary thyroid cancer (MTC) is incurable and FDA-approved kinase inhibitors that include oncogenic RET as a target do not result in complete responses. Association studies of human MTCs and murine models suggest that the CDK/RB pathway may be an alternative target. The objective of this study was to determine if CDKs represent therapeutic targets for MTC and to define mechanisms of activity. Using human MTC cells that are either sensitive or resistant to vandetanib, we demonstrate that palbociclib (CDK4/6 inhibitor) is not cytotoxic to MTC cells but that they are highly sensitive to dinaciclib (CDK1/2/5/9 inhibitor) accompanied by reduced CDK9 and RET protein and mRNA levels. CDK9 protein was highly expressed in 83 of 83 human MTCs and array-comparative genomic hybridization had copy number gain in 11 of 30 tumors. RNA sequencing demonstrated that RNA polymerase II-dependent transcription was markedly reduced by dinaciclib. The CDK7 inhibitor THZ1 also demonstrated high potency and reduced RET and CDK9 levels. ChIP-sequencing using H3K27Ac antibody identified a superenhancer in intron 1 of RET. Finally, combined inhibition of dinaciclib with a RET kinase inhibitor was synergistic. In summary, we have identified what we believe is a novel mechanism of RET transcription regulation that potentially can be exploited to improve RET therapeutic targeting.

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Mechanism of Oncogene Addiction

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Transcriptional Targeting Of Oncogene Addiction In Medullary Thyroid Cancer

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

2018-12-25 | GSE114070 | GEO

microRNA profile of human medullary thyroid cancer

Project description:To identify a microRNA profile of human medullary thyroid cancer (MTC), we performed a miRNA microarray analysis exploiting 8 primary tumours and 9 paired neck nodes metastases in comparison with 3 non-neoplastic thyroid tissues.

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Project description:Medullary thyroid cancer (MTC) accounts for less than 5% of all thyroid cancers, and it is a rare neuroendocrine tumor which derives from calcitonin-secreting thyroid C cells.Given the underlying mechanism involved in MTC remain unclear, the development and the specific pathways of MTC require further investigation.here we employed the application of TMT6plex-based LC-MS/MS to identify and analyze the novel differentially-expressed proteins(DEPs) from MTC patients, To our best knowledge, it is the first study to comprehensively investigate the molecular mechanisms of MTC by proteomics technology from Chinese MTC patients’ tissues, and these DEPs identified in our study will provide a better understanding of the underlying pathophysiology of MTC, as well as may provide potential therapeutic targets for patients with MTC.

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