Pharmacological blockade of high-risk MYCN driven neuroblastoma using an orally-bioavailable CDK2/9 inhibitor
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PROVIDER: PRJNA605838 | ENA |
REPOSITORIES: ENA
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Project description:Pharmacological blockade of high-risk MYCN driven neuroblastoma using an orally-bioavailable CDK2/9 inhibitor
| PRJNA527249 | ENA
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
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 | GSE128330 | GEO
Project description:Neuroblastoma (NB) is a paediatric tumor wherein amplification of the oncogenic basic helix-loop-helix (bHLH) transcription factor (TF) MYCN confers clinical and biologic features prototypical of Myc-dependent cancers. TF-dependent cancers like MYCN-amplified NB are difficult to target, but the availability of clinical-candidate transcription inhibitors makes selective blockade of oncogenic TF activity a possibility. Here we investigated whether NB could be controlled via dual targeting of the transcription elongation machinery and cell cycle progression, using an orally bioavailable and selective CDK9/2 inhibitor CYC065. CYC065 blocks nascent transcription and leads to a drastic reduction in steady-state levels of short-lived transcripts. In MYCN-amplified NB, CYC065 rapidly and completely eliminated MYCN mRNA and protein, terminating expression of a MYCN-dependent gene expression programme. This result is phenocopied by multiple clinical-candidate CDK9 chemical inhibitors and genetic manipulation of CDK9. Mechanistically, CYC065 dissociates MYCN from physical proximity of P-TEFb in cells. P-TEFb co-occupies promoters and enhancers of de-differentiating pathway genes highly-occupied by MYCN, and CDK9 inhibition terminates expression of these and other highly transcribed genes. Intriguingly, targeted inhibition of CDK9 alone is insufficient to eradicate MYCN-dependent cells lines as CDK9 loss alone is compensated by upregulation of CDK2. CYC065 targeted MYCN-driven neuroblastoma in vivo, resulted in tumor regression or eradication and prolonged survival in multiple NB models, and was effective against a wide range of Myc-dependent cancer cells lines in vitro. The data establish that combined CDK9/CDK2 inhibition blocks transcriptional dependence induced by MYCN, highlighting a potential clinical strategy by which many Myc-driven cancers could be targeted.
2019-01-01 | GSE107126 | GEO
Project description:Blockade of MYCN-dependent transcription using orally-bioavailable CDK9 inhibitors
| PRJNA350621 | ENA
Project description:Two genes have a synthetic lethal relationship when silencing or inhibition of one gene is only lethal in the context of a mutation or activation of the second gene. This situation offers an attractive therapeutic strategy, as inhibition of such a gene will only trigger cell death in tumor cells with an activated second oncogene but spare normal cells without activation of the second oncogene. Here we present evidence that CDK2 is synthetic lethal to neuroblastoma cells with MYCN amplification and overexpression. Neuroblastomas are childhood tumors with an often lethal outcome. Twenty percent of the tumors have MYCN amplification and these tumors are ultimately refractory to any therapy. Targeted silencing of CDK2 by three RNA interference techniques induced apoptosis in MYCN-amplified neuroblastoma cell lines, but not in MYCN single copy cells. Silencing of MYCN abrogated this apoptotic response in MYCN-amplified cells. Inversely, silencing of CDK2 in MYCN single copy cells did not trigger apoptosis, unless a MYCN transgene was activated. The MYCN induced apoptosis after CDK2 silencing was accompanied by nuclear stabilization of P53 and mRNA profiling showed up-regulation of P53 target genes. Silencing of P53 rescued the cells from MYCN-driven apoptosis. The synthetic lethality of CDK2 silencing in MYCN activated neuroblastoma cells can also be triggered by inhibition of CDK2 with a small molecule drug. Treatment of neuroblastoma cells with Roscovitine, a CDK inhibitor, at clinically achievable concentrations induced MYCN-dependent apoptosis. The synthetic lethal relation between CDK2 and MYCN indicates CDK2 inhibitors as potential MYCN-selective cancer therapeutics. CDK2 shRNA in a tet repressor system was stably transfected in the IMR32 cell line. Time course analysis was performed in triplicate after induction of CDK2 shRNA at 5 time points.
2014-05-19 | E-GEOD-16480 | biostudies-arrayexpress
Project description:Pharmacological blockade of MYCN in neuroblastoma using orally-bioavailable CDK inhibitors reveals an approach widely applicable to Myc-dependent cancers
| PRJNA419129 | ENA
Project description:Two genes have a synthetic lethal relationship when silencing or inhibition of one gene is only lethal in the context of a mutation or activation of the second gene. This situation offers an attractive therapeutic strategy, as inhibition of such a gene will only trigger cell death in tumor cells with an activated second oncogene but spare normal cells without activation of the second oncogene. Here we present evidence that CDK2 is synthetic lethal to neuroblastoma cells with MYCN amplification and overexpression. Neuroblastomas are childhood tumors with an often lethal outcome. Twenty percent of the tumors have MYCN amplification and these tumors are ultimately refractory to any therapy. Targeted silencing of CDK2 by three RNA interference techniques induced apoptosis in MYCN-amplified neuroblastoma cell lines, but not in MYCN single copy cells. Silencing of MYCN abrogated this apoptotic response in MYCN-amplified cells. Inversely, silencing of CDK2 in MYCN single copy cells did not trigger apoptosis, unless a MYCN transgene was activated. The MYCN induced apoptosis after CDK2 silencing was accompanied by nuclear stabilization of P53 and mRNA profiling showed up-regulation of P53 target genes. Silencing of P53 rescued the cells from MYCN-driven apoptosis. The synthetic lethality of CDK2 silencing in MYCN activated neuroblastoma cells can also be triggered by inhibition of CDK2 with a small molecule drug. Treatment of neuroblastoma cells with Roscovitine, a CDK inhibitor, at clinically achievable concentrations induced MYCN-dependent apoptosis. The synthetic lethal relation between CDK2 and MYCN indicates CDK2 inhibitors as potential MYCN-selective cancer therapeutics.
2014-05-19 | GSE16480 | GEO
Project description:Neuroblastoma is a common solid tumor that accounts for 15% of cancer deaths in children and amplification of the MYCN oncogene is the most common genomic alteration in aggressive tumors. Although MYCN is expressed as a tumor-specific oncoprotein in poor-outcome neuroblastoma, making it a therapeutic target of great potential importance, no drugs with significant activity against MYCN or MYC are available for clinical use. The aim of this study was to explore the sensitivity of neuroblastoma cells in vitro and in vivo to the tri-substituted purine CDK inhibitors, CYC065, chemical analogues of seliciclib, (Cyclacel Ltd).
2020-08-01 | GSE89197 | GEO
Project description:Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets to provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit the target and an E3 ligase, resulting in ubiquitylation and proteosome-dependent degradation of the target. The oral route of administration is the option of choice in the clinic, but has only been achieved so far by CRBN- recruiting bifunctional degrader molecules. We aimed to achieve orally bioavailable molecules that selectively degrade the BAF Chromatin Remodelling complex ATPase SMARCA2 over its closely related paralogue SMARCA4, to allow in vivo evaluation of the synthetic lethality concept of SMARCA2 dependency in SMARCA4 deficient cancers. Here we outline structure- and property-guided approaches that led to the first orally bioavailable VHL-recruiting degraders. Our tool compound, ACBI2, shows selective degradation of SMARCA2 over SMARCA4 in ex vivo human whole blood assays and in vivo efficacy in SMARCA4-deficient cancer models. This study demonstrates the feasibility for broadening the E3 ligase and physicochemical space that can be utilised for achieving oral efficacy with bifunctional molecules.
2022-06-20 | PXD032239 | Pride