SR-4835 in ovarian cancer
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ABSTRACT:
PROVIDER: PRJEB93935 | ENA |
REPOSITORIES: ENA
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Project description:CDK12/13 are transcriptional cyclin-dependent kinases shown to phosphorylate the C-terminal domain of RNA polymerase II. Here, we investigated the changes on the transcriptome level after inhibition of CDK12/13 by the specific inhibitor SR-4835 in a panel of ovarian cancer cell lines: SK-OV-3, A2780, A2780 cis, Caov-3, Caov-3 cis. All cell lines were treated for 24h with 90 nM SR-4835 prior RNA extraction and paired-end RNA sequencing. Differential gene expression, Ingenuity pathway analysis and genes with alternative exon usage was determined.
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Project description:Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play pivotal roles in orchestrating transcription elongation, DNA damage response, and maintenance of genomic stability. Aberrant CDK12 expression, homozygous loss, and mutations have been documented in various malignancies. Previous studies have demonstrated CDK12 and 13 are promising therapeutic targets in cancer. In this study, we developed a selective CDK12/13 PROTAC degrader YJ9069, which in a panel of cancer cell lines, affirm its effectiveness in inhibiting cell proliferation in subsets of cancer. CDK12/13 degradation rapidly triggers gene-length dependent transcriptional elongation defects, leading to DNA damage and cell cycle arrest. In vivo, YJ9069 significantly suppresses tumor growth in prostate cancer cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Modifications of YJ9069 yielded a first-in-class orally bioavailable CDK12/13 degrader, YJ1206, which exhibits a comparable efficacy with significantly less toxicity. To identify pathways that may be synthetically lethal upon CDK12/13 degradation, we screened phosphorylation pathway arrays employing cell lines treated with YJ1206. Interestingly, degradation or genetic knock-down of CDK12/13, led to activation of the Akt pathway. Degradation of CDK12/13 with YJ1206, combined with AKT pathway inhibition with uprosertib, led to a striking synthetic lethal effect in pre-clinical models of prostate cancer. Taken together, these studies demonstrate that combination CDK12/13 and AKT pathway antagonism induces drug-drug synthetic lethality.
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Project description:Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play pivotal roles in orchestrating transcription elongation, DNA damage response, and maintenance of genomic stability. Aberrant CDK12 expression, homozygous loss, and mutations have been documented in various malignancies. Previous studies have demonstrated CDK12 and 13 are promising therapeutic targets in cancer. In this study, we developed a selective CDK12/13 PROTAC degrader YJ9069, which in a panel of cancer cell lines, affirm its effectiveness in inhibiting cell proliferation in subsets of cancer. CDK12/13 degradation rapidly triggers gene-length dependent transcriptional elongation defects, leading to DNA damage and cell cycle arrest. In vivo, YJ9069 significantly suppresses tumor growth in prostate cancer cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Modifications of YJ9069 yielded a first-in-class orally bioavailable CDK12/13 degrader, YJ1206, which exhibits a comparable efficacy with significantly less toxicity. To identify pathways that may be synthetically lethal upon CDK12/13 degradation, we screened phosphorylation pathway arrays employing cell lines treated with YJ1206. Interestingly, degradation or genetic knock-down of CDK12/13, led to activation of the Akt pathway. Degradation of CDK12/13 with YJ1206, combined with AKT pathway inhibition with uprosertib, led to a striking synthetic lethal effect in pre-clinical models of prostate cancer. Taken together, these studies demonstrate that combination CDK12/13 and AKT pathway antagonism induces drug-drug synthetic lethality.
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Project description:To understand the differentiation of ovarian cancer stem cells (CSCs), We derived two phenotypes of CSCs and identified the gene expression profiling. The CSCs were derived from Cp70 ovarian cancer cells and cultured in suspension and examined every day for sphere formation. Spheres were then dissociated and passaged at least eight times in 2 months to generate spheres, which are henceforth referred to as SR cells. The surface of SR-I was smooth regardless of the size, whereas SR-II was morula. SR-I could differentiate into multiple-lineage cell types under specific induction conditions. SR-I spheroids could differentiate to SR-II spheroids through epithelial-mesenchymal transition.The self-renewal was slower for SR-I than for SR-II.
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