Digital gene expression (DGE) based transcript profiling of CDK inhibitors
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE125215 | GEO | 2019/06/27
REPOSITORIES: GEO
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Project description:Digital gene expression (DGE) based transcript profiling of CDK inhibitors
| PRJNA515531 | ENA
Project description:This SuperSeries is composed of the following subset Series: GSE18486: CDK inhibitors PHA-848125 and PHA-690509 profiling on A2780 GSE18498: CDK inhibitor PHA-793887 profiling on A2780 GSE18501: CDK inhibitor PHA-848125 gene expression profiling on MCF7 cell line GSE18504: Flavopiridol profiling on A2780 GSE19638: Compounds profiling on MCF7 Refer to individual Series
2010-07-14 | E-GEOD-18552 | biostudies-arrayexpress
Project description:The effects of the CDK inhibitors PHA-848125 and PHA-690509 on the A2780 cell line were analysed by gene expression profiling. The A2780 cell line was treated with PHA-848125 (CDk-125) or PHA-690509 (CDk-509) for 6 hours at a dose equal to 5 times the IC50. Untreated A2780 cells were used as a control. Three replicates per treatment.
2010-07-14 | E-GEOD-18486 | biostudies-arrayexpress
Project description:The effects of the CDK inhibitors PHA-848125 and PHA-690509 on the A2780 cell line were analysed by gene expression profiling.
2010-07-14 | GSE18486 | GEO
Project description:Type II testicular germ cell tumors (TGCT) are the most frequently diagnosed solid malignancy in young men. Up to 15 % of patients with metastatic non-seminomas show cisplatin resistance having a very poor survival rate due to lacking treatment options. Transcriptional cyclin-dependent kinases (CDK) have been shown to be effective targets in treatment of different types of cancer. Here, we investigated the effects of the CDK inhibitors dinaciclib, flavopiridol, YKL-5-124, THZ1, NVP2, SY0351 and THZ531. XTT viability assay revealed strong cytotoxic impact of CDK7/ 12/ 13 inhibitor SY0351 and CDK9 inhibitor NVP2 on the TGCT wild type cell lines (2102EP, NCCIT, TCam2) and the cisplatin resistant cell lines (2102EP-R, NCCIT-R). The CDK7 inhibitor YKL-5-124 showed strong impact on 2102EP, 2102EP-R, NCCIT and NCCIT-R cell lines leaving the MPAF control cell line mostly unaffected. FACS based analysis revealed mild effects on the cell cycle of 2102EP and TCam2 cells after SY0351, YKL-5-124 or NVP2 treatment. Molecular analysis showed a cell line specific response for SY0351 and NVP2 inhibition while YKL-5-124 induced similar molecular changes in 2102EP, TCam2 and MPAF cells. Thus, after TGCT subtype determination CDK inhibitors might be a potential alternative for optimized and individualized therapy independent of chemotherapy sensitivity.
2022-03-26 | GSE198248 | GEO
Project description:Cyclin dependent kinase 4 and 6 (CDK4/6) in complex with D-type cyclins promote cell cycle entry, at least in part through phosphorylation of the retinoblastoma tumor suppressor protein (Rb). The CDK4/6-cyclin D-Rb pathway is commonly deregulated in human cancer, often through CDK4/6 or D-type cyclin overexpression, or inactivation of the CDK4/6 antagonist p16/CDKN2A. Importantly, a substantial fraction of cancers depend on continuous CDK4/6-cyclin D kinase activity and are sensitive to CDK4/6-specific inhibitors. Here, we investigate critical CDK4/6-cyclin D functions that may determine the sensitivity to CDK4/6 inhibitors, making use of the essential roles of CDK4/6 (CDK-4) and cyclin D (CYD-1) in the nematode C. elegans. In an unbiased screen, we found that simultaneous loss of C. elegans Rb (lin-35) and down-regulation of the APC/C substrate specificity factor FZR1/Cdh1 completely overcomes CDK-4/CYD-1 requirement. Furthermore, CDK-4/CYD-1 phosphorylates specific residues in the LIN-35 Rb spacer domain and FZR-1 N-terminus that correspond to inactivating phosphorylations of the human homologs. Thus, CDK-4/CYD-1 appears to promote cell cycle entry by antagonizing not only transcriptional repression by LIN-35 Rb but also protein degradation by APC/CFZR-1. Simultaneous knockdown of Rb and FZR1 in human breast cancer cells synergistically overcomes arrest by the CDK4/6-specific inhibitor PD 00332991. These results reveal APC/CFZR1 as a putative CDK4/6-Cyclin D target and important contributing factor in the response to CDK4/6-inhibitor treatment.
2016-07-05 | PXD001501 | Pride
Project description:Transcriptional CDK inhibitors as potential treatment option for testicular germ cell tumors
| PRJNA814284 | ENA
Project description:Cyclin dependent kinase 9 (CDK9), a key regulator of transcriptional elongation, has long been considered a promising target for cancer therapy, particularly for cancers driven by transcriptional dysregulation. However, despite promising early clinical data in blood cancers using pan-CDK inhibitors that potently inhibit CDK9 such as Dinaciclib and Flavopiridol, no selective CDK9 inhibitors have been clinically approved. Here we show that a multi-targeted CDK inhibitor can be used to develop a selective CDK9 degrader exemplified by THAL-SNS-032, a hetero-bifunctional molecule composed of SNS-032, a CDK2,7,9 inhibitor conjugated to thalidomide, a small molecule binder of Cereblon. We demonstrate that THAL-SNS-032 can recruit the E3 ubiquitin ligase Cereblon to CDK9 and induce its proteasome-mediated degradation. Treatment of cells with low nanomolar concentrations of THAL-SNS-032 resulted in rapid and efficient CDK9 degradation but did not affect levels of other SNS-032 targets, including CDK2 and CDK7. Consistent with this selective degradation phenotype, transcriptional profiling of THAL-SNS-032 indicated that its transcriptional effects were more similar to that of a selective CDK9 inhibitor, NVP2, than that of the nonselective SNS-032 parent compound. Moreover, THAL-SNS-032, in contrast to traditional CDK9 inhibitors, retained potent pro-apoptotic activity even after compound removal from cells. This suggests that degradation of CDK9 leads to prolonged cytotoxic effects as compared to CDK9 inhibition. Thus, our findings suggest that thalidomide conjugation may be a promising strategy for converting multi-targeting inhibitors into selective degraders, and that the pharmacological effects of kinase degradation can be distinct from kinase inhibition.
2017-09-01 | GSE89385 | GEO
Project description:Cyclin dependent kinase 9 (CDK9), a key regulator of transcriptional elongation, has long been considered a promising target for cancer therapy, particularly for cancers driven by transcriptional dysregulation. However, despite promising early clinical data in blood cancers using pan-CDK inhibitors that potently inhibit CDK9 such as Dinaciclib and Flavopiridol, no selective CDK9 inhibitors have been clinically approved. Here we show that a multi-targeted CDK inhibitor can be used to develop a selective CDK9 degrader exemplified by THAL-SNS-032, a hetero-bifunctional molecule composed of SNS-032, a CDK2,7,9 inhibitor conjugated to thalidomide, a small molecule binder of Cereblon. We demonstrate that THAL-SNS-032 can recruit the E3 ubiquitin ligase Cereblon to CDK9 and induce its proteasome-mediated degradation. Treatment of cells with low nanomolar concentrations of THAL-SNS-032 resulted in rapid and efficient CDK9 degradation but did not affect levels of other SNS-032 targets, including CDK2 and CDK7. Consistent with this selective degradation phenotype, transcriptional profiling of THAL-SNS-032 indicated that its transcriptional effects were more similar to that of a selective CDK9 inhibitor, NVP2, than that of the nonselective SNS-032 parent compound. Moreover, THAL-SNS-032, in contrast to traditional CDK9 inhibitors, retained potent pro-apoptotic activity even after compound removal from cells. This suggests that degradation of CDK9 leads to prolonged cytotoxic effects as compared to CDK9 inhibition. Thus, our findings suggest that thalidomide conjugation may be a promising strategy for converting multi-targeting inhibitors into selective degraders, and that the pharmacological effects of kinase degradation can be distinct from kinase inhibition.
2017-09-01 | GSE89384 | GEO
Project description:Androgen-deprivation therapy is a standard treatment for advanced prostate cancer. However, most patients eventually acquire resistance and progress to castration-resistant prostate cancer (CRPC). In this study, we established new CRPC cell lines, AILNCaP14 and AILNCaP15, from LNCaP cells under androgen-deprived conditions. Unlike most pre-existing CRPC cell lines, both cell lines expressed higher levels of androgen receptor (AR) and prostate-specific antigen (PSA) than parental LNCaP cells. Moreover, these cells exhibited primary resistance to enzalutamide. Since AR signaling plays a significant role in the development of CRPC, PSA promoter sequences fused with GFP were introduced into AILNCaP14 cells to conduct GFP fluorescence-based chemical screening. We identified flavopiridol, a broad spectrum CDK inhibitor, as a candidate drug that could repress AR transactivation of CRPC cells, presumably through the inhibition of phosphorylation of AR on the serine 81 residue (pARSer81). Importantly, this broad spectrum CDK inhibitor inhibited the proliferation of AILNCaP14 cells both in vitro and in vivo. Moreover, a newly developed liver metastatic model using AILNCaP15 cells revealed that the compound attenuated tumor growth of CRPC harboring highly metastatic properties. Finally, we developed a patient-derived xenograft (PDX) model of CRPC and DCaP CR from a patient presenting therapeutic resistance to enzalutamide, abiraterone, and docetaxel. Flavopiridol successfully suppressed the tumor growth of CRPC in this PDX model. Since ARSer81 was found to be phosphorylated in clinical CRPC samples, our data suggested that broad spectrum CDK inhibitors, might be a potent candidate drug for the treatment of CRPC, including those exhibiting primary resistance to enzalutamide.
2024-02-28 | GSE258991 | GEO