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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.
| S-EPMC6141185 | biostudies-literature
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 | GSE114068 | GEO
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
Project description:Transcriptional Targeting Of Oncogene Addiction In Medullary Thyroid Cancer
| PRJNA464052 | ENA
Project description:Transcriptional Targeting Of Oncogene Addiction In Medullary Thyroid Cancer [RNA-Seq]
| PRJNA464055 | ENA
Project description:Transcriptional Targeting Of Oncogene Addiction In Medullary Thyroid Cancer [ChIP-Seq]
| PRJNA464056 | ENA
Project description:Thyroid carcinoma (TC) is the most common malignancy of endocrine organs with an increasing incidence in industrialized countries. The majority of TC are characterized by a good prognosis, even though cases with aggressive forms not cured by standard therapies are also present. Moreover, target therapies have led to low rates of partial response and prompted the emergence of resistance, indicating that new therapies are needed. In this review, we summarize current literature about the non-oncogene addiction (NOA) concept, which indicates that cancer cells, at variance with normal cells, rely on the activity of genes, usually not mutated or aberrantly expressed, essential for coping with the transformed phenotype. We highlight the potential of non-oncogenes as a point of intervention for cancer therapy in general, and present evidence for new putative non-oncogenes that are essential for TC survival and that may constitute attractive new therapeutic targets.
| S-EPMC7017043 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-03-20 | GSE75058 | GEO
Project description:While Next-Generation Sequencing (NGS) and technological advances have been useful in identifying genetic profiles of tumorigenesis, novel target proteins and various clinical biomarkers, cancer continues to be a major global health threat. DNA replication, DNA damage response (DDR) and repair, and cell cycle regulation continue to be essential systems in targeted cancer therapies. Although many genes involved in DDR are known to be tumor suppressor genes, cancer cells are often dependent and addicted to these genes, making them excellent therapeutic targets. In this review, genes implicated in DNA replication, DDR, DNA repair, cell cycle regulation are discussed with reference to peptide or small molecule inhibitors which may prove therapeutic in cancer patients. Additionally, the potential of utilizing novel synthetic lethal genes in these pathways is examined, providing possible new targets for future therapeutics. Specifically, we evaluate the potential of TONSL as a novel gene for targeted therapy. Although it is a scaffold protein with no known enzymatic activity, the strategy used for developing PCNA inhibitors can also be utilized to target TONSL. This review summarizes current knowledge on non-oncogene addiction, and the utilization of synthetic lethality for developing novel inhibitors targeting non-oncogenic addiction for cancer therapy.
| S-EPMC7909239 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-12-23 | E-GEOD-50625 | biostudies-arrayexpress