CDK10 suppression sensitizes cells to CDK12/13 blockade
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE307213 | GEO | 2026/06/09
REPOSITORIES: GEO
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Project description:CDK10 suppression sensitizes cells to CDK12/13 blockade
| PRJNA1314771 | ENA
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:To assess changes in the nascent and steady state transcriptomes after treatment with the CDK12/13 inhibitor THZ531, we performed SLAM-seq in the G7 glioblastoma derived cell line after DMSO treatment or treatment with 500 nM THZ531 for 6 hrs.
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Project description:Inactivation of cyclin-dependent kinase 12 (CDK12) characterizes an immunogenic molecular subtype of prostate cancer, marked by genomic instability and increased intratumoral T cell infiltration. However, the mechanisms underlying this phenotype and its therapeutic implications remain unclear. Here, we demonstrate that CDK12 inactivation or suppression of its paralog CDK13 activates stimulator of interferon genes (STING) signaling across multiple cancer types. Analysis of clinical cohorts receiving immune checkpoint blockade (ICB) revealed that reduced CDK12/13 expression correlates with improved survival and treatment response. Mechanistically, CDK12/13 depletion or targeted degradation induces transcription-replication conflicts and R-loop accumulation, triggering cytosolic DNA release and subsequent STING activation. Functionally, CDK12/13 degradation significantly delays tumor growth and exhibits synergistic effects with anti-PD1 therapy in various syngeneic tumor models. This combination enhances STING activity and promotes the infiltration and activation of CD8+ T cells within tumors. Notably, the anti-tumor effects of this combination require STING signaling and functional CD8+ T cells. These findings identify CDK12/13 as promising therapeutic targets for enhancing ICB efficacy, highlighting their potential to amplify STING-mediated anti-tumor immunity. This work provides a mechanistic framework for leveraging CDK12/13 antagonists in combination with ICB to improve clinical outcomes in cancer therapy.
2025-06-23 | GSE283227 | GEO
Project description:Inactivation of cyclin-dependent kinase 12 (CDK12) characterizes an immunogenic molecular subtype of prostate cancer, marked by genomic instability and increased intratumoral T cell infiltration. However, the mechanisms underlying this phenotype and its therapeutic implications remain unclear. Here, we demonstrate that CDK12 inactivation or suppression of its paralog CDK13 activates stimulator of interferon genes (STING) signaling across multiple cancer types. Analysis of clinical cohorts receiving immune checkpoint blockade (ICB) revealed that reduced CDK12/13 expression correlates with improved survival and treatment response. Mechanistically, CDK12/13 depletion or targeted degradation induces transcription-replication conflicts and R-loop accumulation, triggering cytosolic DNA release and subsequent STING activation. Functionally, CDK12/13 degradation significantly delays tumor growth and exhibits synergistic effects with anti-PD1 therapy in various syngeneic tumor models. This combination enhances STING activity and promotes the infiltration and activation of CD8+ T cells within tumors. Notably, the anti-tumor effects of this combination require STING signaling and functional CD8+ T cells. These findings identify CDK12/13 as promising therapeutic targets for enhancing ICB efficacy, highlighting their potential to amplify STING-mediated anti-tumor immunity. This work provides a mechanistic framework for leveraging CDK12/13 antagonists in combination with ICB to improve clinical outcomes in cancer therapy.
2025-06-23 | GSE283088 | GEO
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.
2024-08-14 | GSE262120 | GEO
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.
2024-08-14 | GSE262119 | GEO
Project description:The efficacy of KRAS-G12C inhibitors in lung cancer is limited by the rapid onset of acquired resistance. While divergent mechanisms of resistance across patients and preclinical models have complicated efforts to identify therapeutic strategies for sotorasib-resistant cancers, we found that sotorasib-resistant H358 and LU65 cell lines, which have distinct mechanisms of resistance and drug sensitivity profiles, both exhibited increased vulnerability to treatment with SR-4835, an inhibitor of the transcriptional kinases CDK12 and CDK13. To identify CDK12/13-dependent genes linked to the increased sensitivity we observed in sotorasib-resistant over parental cells, we treated parental and sotorasib-resistant H358 and LU65 cells with SR-4835 and performed RNA sequencing.
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Project description:Adenocarcinoma of the ovary is the fifth leading cause of cancer death among American women. Most mortality results from high-grade serous ovarian carcinoma (HGS-OvCa)—a disease type resistant to conventional chemotherapy, and therein requiring urgent preclinical modeling for pharmaceutical testing. We generated a novel serous ovarian carcinoma model by employing Ovgp1-driven Cre recombinase to catalyze CRISPR-Cas9-medicated ablation of the Trp53, Rb1 and Nf1 tumor suppressor genes in the mouse ovary (m-sgPRN mice). The gene encoding cyclin dependent kinase 12 (CDK12) is among the most frequently inactivated in HGS-OvCa. Its loss corresponds with increased mortality, DNA damage (including tandem duplications) and tumor immunogenicity. Co-ablation of Cdk12 in the m-sgPRN model (m-sgPRN; Cdk12KO mice) accelerated tumor progression leading to bona fide HGS-OvCa, and early mortality. In a conventional (Cre-lox-medicated) Trp53/ Nf1/ Rb1 triple knockout model, Cdk12 ablation (PRN; Cdk12KO mice) effected immune infiltration characterized by CD3, CD8, CD4, and Granzyme B positivity like that seen in clinical HGS-OvCa. We observed recapitulation of this immunogenic phenotype—with corresponding sensitivity to immune checkpoint blockade—in a novel syngeneic allograft model derived from these animals. To screen for synthetic lethal interactions with Cdk12 loss, we conducted a CRISPR-Cas9 screen in PRN; Cdk12KO cell lines. The gene encoding CDK12 paralog CDK13 emerged as the most depleted, suggesting CDK13 could be targeted to promote paralog-induced synthetic lethality as previously demonstrated in CDK12-mutant prostate cancer. Indeed, m-sgPRN; Cdk12KO and PRN; Cdk12KO -derived cell lines exhibited enhanced sensitivity to the CDK13/12 degrader YJ1206. Our work defines CDK13-targeting as a novel treatment modality for CDK12-inactive HGS-OvCa while establishing biological resources for the in vivo modeling of this disease.
2025-05-23 | GSE284088 | GEO
Project description:To assess RNA Pol II (RNAPII) enrichment and modification state after treatment with the CDK12/13 inhibitor THZ531, we performed Cut&Run using antibodies against RNAPII as well as phosphorylated Serine 2 (S2P) or Serine 5 (S5P) in the c-terminal domain of RNAPII in the G7 glioblastoma derived cell line after DMSO treatment or treatment with THZ531 for 1 hr or 6 hrs. In addition, we performed Cut&Run of the H3K27me3 and H3K27Ac histone marks in untreated cells.
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