Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Co-targeting CDK7/CDK9 and CKIα exerts efficacious anticancer effects against TERT gene-rearranged neuroblastoma

ABSTRACT: TERT gene rearrangement with transcriptional super-enhancers leads to substantial TERT over-expression and neuroblastoma. No targeted therapy is available for clinical trials in patients. Here we show that the transcriptional kinases CDK7/CDK9 and the casein kinase CKIα were required for TERT gene over-expression and p53 protein degradation respectively in TERT-rearranged neuroblastoma cells. Co-knockdown of CDK7/CDK9 and CKIα or treatment with the CDK7/CDK9 and CKIα co-inhibitor A51 reduced TERT gene transcriptional initiation, elongation and expression, activated p53 protein expression, co-operatively induced apoptosis and suppressed tumor progression in mouse models. Screening of an approved oncology drug library identified Ceritinib as the agent exerting the best synergistic anticancer effects with A51. A51 and Ceritinib synergistically down-regulated mitochondrial complex I gene expression and induced oxidative stress and TERT-rearranged neuroblastoma cell apoptosis. In mice xenografted with TERT-rearranged patient-derived xenograft neuroblastoma cells, A51 and Ceritinib synergistically induced tumor cell apoptosis, suppressed tumor progression and improved mouse survival. A51 and Ceritinib combination therapy is therefore a good candidate for translation into the first clinical trial of a targeted therapy against TERT-rearranged neuroblastoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE262443 | GEO | 2026/04/08

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Co-targeting CDK7/CDK9 and CKIα exerts efficacious anticancer effects against TERT gene-rearranged neuroblastoma

Project description:Co-targeting CDK7/CDK9 and CKIα exerts efficacious anticancer effects against TERT gene-rearranged neuroblastoma

| PRJNA1091879 | ENA

Genome-wide maps of chromatin state in primary MLL-AF9 AML

Project description:Here we describe the development of CKIα inhibitors, which co-target the transcriptional kinases CDK7 and CDK9, thereby augmenting CKIα-induced p53 activation and its anti-leukemic activity. Oncogene-driving super-enhancers (SEs) are highly sensitive to CDK7/9 inhibition. We identified multiple newly-gained SEs in primary mouse AML cells and demonstrate that the inhibitors abolish many SEs and preferentially suppress the transcription elongation of SE-driven oncogenes. We show that blocking CKIα together CDK7 and/or CDK9 synergistically stabilize p53, deprive leukemia cells of survival and proliferation-maintaining SE-driven oncogenes, and induce apoptosis.

2018-08-23 | GSE117443 | GEO

HDAC inhibition suppresses telomerase activity in neuroblastoma cells harboring TERT rearrangements [array]

Project description:Genome wide DNA methylation profiling of high-risk TERT-rearranged neuroblastoma cells treated with solvent or HDAC inhibitor panobinostat. The Illumina HumanMethylation EPIC Beadchip was used to obtain DNA methylation profiles. Samples included 3 solvent treated samples and 3 panobinostat-treated samples after 18 h of treatment.

2022-08-04 | GSE155703 | GEO

Brd4, H3K27Ac, and H3K36me3 binding profiles with or without Dinaciclib in human neuroblastoma CLB-GA cells

Project description:Promoter rearrangement of the telomerase reverse transcriptase (TERT) gene juxtaposes the coding sequence to strong enhancer elements, leading to TERT overexpression and poor prognosis. TERT associated oncogenic signaling in neuroblastoma remains unclear. Gene set enrichment analysis of RNA-seq data from 498 neuroblastoma patients revealed a coordinated activation of oncogenic signaling pathways and differentially overexpressed gene signature in a subgroup of MycN non-amplified neuroblastomas with TERT overexpression. ChIP-seq analysis of human neuroblastoma cell line CLB-GA harboring TERT rearrangement uncovered genome-wide chromatin co-occupancy of Brd4 and H3K27Ac and robust enrichment of H3K36me3 in TERT and multiple TERT-associated genes. We demonstrated a critical regulatory role of Brd4 and cyclin-dependent kinases in the expression and chromatin activation. Inhibition of both with AZD5153 and dinaciclib proved most effective in tumor growth suppression of neuroblastoma cell lines, primary cells, and xenograft. Our study provides a therapeutic strategy utilizing epigenetic targeting of neuroblastoma with TERT overexpression.

2020-05-12 | GSE133453 | GEO

Fibroblast growth factor receptor 3 overexpression mediates ALK inhibitor resistance in ALK-rearranged non-small cell lung cancer

Project description:The rearrangement of anaplastic lymphoma kinase (ALK) occurs in 3%-5% of patients with non-small cell lung cancer (NSCLC) and confers sensitivity to ALK-tyrosine kinase inhibitors (TKIs). For the treatment of patients with ALK-rearranged NSCLC, various additional ALK-TKIs have been developed. Ceritinib is a second-generation ALK-TKI and has shown great efficacy in the treatment of patients with both newly diagnosed and crizotinib, a first-generation ALK-TKI, refractory ALK-rearranged NSCLC. However, tumors can also develop ceritinib resistance. This may result from secondary ALK mutations, but other mechanisms responsible for this have not been fully elucidated. In this study, we explored the mechanisms of ceritinib resistance by establishing ceritinib-resistant, echinoderm microtubule-associated protein-like 4 (EML4)-ALK-positive H3122 cells and ceritinib-resistant patient-derived cells. We identified a mechanism of ceritinib resistance induced by bypass signals that is mediated by the overexpression and activation of fibroblast growth factor receptor 3 (FGFR3). FGFR3 knockdown by small hairpin RNA or treatment with FGFR inhibitors was found to resensitize the resistant cells to ceritinib in vitro and in vivo. FGFR ligands from either human serum or fetal bovine serum were able to activate FGFR3 and induce ceritinib resistance. A detailed analysis of ceritinib-resistant patient-derived specimens confirmed that tyrosine-protein kinase Met (cMET) amplification induces ceritinib resistance. Amplified cMET counter-activated EGFR and/or Her3, and induced ceritinib resistance. These results reveal multiple ceritinib resistance mechanisms and suggest that ceritinib resistance might be able to overcome by identifying precise resistance mechanisms.

2022-08-14 | GSE77764 | GEO

Pharmacological blockade of high-risk MYCN driven neuroblastoma using an orally-bioavailable CDK2/9 inhibitor

Project description:The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, a paediatric cancer in which MYCN amplification is strongly associated with unfavourable outcome. Here, we show that CYC065, a clinical inhibitor of CDK2 and CDK9, selectively targets MYCN-amplified neuroblastoma via blockade of CDK9-dependent, MYCN-driven transcriptional elongation and CDK2-dependent proliferation. CYC065 also targets nascent transcription of short half-life genes including MYCN and MCL-1 leading to downregulation of MYCN-driven ‘adrenergic’ gene expression programs, growth inhibition, and apoptosis in vitro and in vivo. These data highlight the clinical potential of CDK2/9 inhibition in the treatment of MYCN-amplified neuroblastoma.

2020-10-13 | GSE145068 | GEO

Pharmacological blockade of high-risk MYCN driven neuroblastoma using an orally-bioavailable CDK2/9 inhibitor

2020-10-13 | GSE128330 | GEO

Acute BRCAness Induction and AR Signaling Blockage through CDK12/7/9 Degradation Enhances PARP Inhibitor Sensitivity in Prostate Cancer

Project description:Current treatment strategies for advanced prostate cancer (PCa) primarily rely on androgen receptor (AR)-directed therapies. However, the emergence of castration-resistant prostate cancer (CRPC) and resistance to AR signaling inhibitors (ARSI) pose substantial challenges. This study introduces a triple degrader, BSJ-5-63, targeting CDK12, CDK7, and CDK9, which has the potential to transform CRPC therapy. BSJ-5-63 uniquely downregulates homologous recombination repair (HRR) genes, including BRCA1 and BRCA2, by degrading CDK12, and it also attenuates AR signaling by degrading CDK7 and CDK9, further enhancing BSJ-5-63's therapeutic impact. Importantly, BSJ-5-63 induces a 'BRCAness' state that persists for a significant duration, enabling rational combination therapy with PARP inhibitors (PARPis) while minimizing drug-related toxicity and resistance. In both in vitro and in vivo studies, potent anti-proliferative effects were observed in both AR-positive and -negative CRPC cells. This research presents a promising multi-pronged approach for CRPC treatment, addressing both DNA repair mechanisms and AR signaling, with the potential to benefit a wide range of patients, regardless of their BRCA1/2 mutational status.

2025-04-30 | GSE263218 | GEO

Cdk9 regulates a promoter-proximal checkpoint to modulate RNA Polymerase II elongation rate in fission yeast

Project description:Post-translational modifications of the transcription elongation complex provide mechanisms to fine-tune gene expression, yet their specific impacts on RNA polymerase II regulation remain difficult to ascertain. Here, in Schizosaccharomyces pombe, we examine the role of Cdk9, and related Mcs6/Cdk7 and Lsk1/Cdk12 kinases, on transcription at base-pair resolution with Precision Run-On sequencing (PRO-seq). Within a minute of Cdk9 inhibition, phosphorylation of Pol II-associated factor, Spt5 is undetectable. The effects of Cdk9 inhibition are more severe than inhibition of Cdk7 and Cdk12, resulting in a shift of Pol II towards the transcription start site (TSS). A time course of Cdk9 inhibition reveals that early transcribing Pol II can escape promoter-proximal regions, but with a severely reduced rate of only ~400 bp/min. Our results in fission yeast suggest the existence of a conserved global regulatory checkpoint that requires Cdk9 kinase activity.

2018-01-04 | GSE102308 | GEO

TERT rearrangements are frequent in neuroblastoma and identify aggressive tumors

Project description:Whole genome sequencing detected structural rearrangements of TERT in 17/75 high stage neuroblastoma with 5 cases resulting from chromothripsis. Rearrangements were associated with increased TERT expression and targeted immediate up- and down-stream regions of TERT, placing in 7 cases a super-enhancer close to the breakpoints. TERT rearrangements (23%), ATRX deletions (11%) and MYCN amplifications (37%) identify three almost non-overlapping groups of high stage neuroblastoma, each associated with very poor prognosis

2015-10-21 | GSE73537 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data