Gene expression profiling of 22Rv1 cells treated with a CDK9 degrader, Compound 45 (D45)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE288031 | GEO | 2026/06/27
REPOSITORIES: GEO
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Project description:Gene expression profiling of 22Rv1 cells treated with a CDK9 degrader, Compound 45 (D45)
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Project description:Triple-negative breast cancer (TNBC) is highlyaggressive with very limited treatment options due to the lack of efficient targeted therapies and thus still remains clinically challenging. Targeting CDK9 to remodel transcriptional regulation shows great promisein cancer therapy. We synthesized new series of heterobifunctional molecules ashighly selective and efficacious CDK9 degraders, enabling potentinhibition of TNBC cell growth and rapidly targeted degradationof CDK9. Moreover, the CDK9 degrader (compound 28) was used to treat on TNBC cell lines and the gene expression profile was performed by RNA-seq.
2024-11-27 | GSE282602 | GEO
Project description:Cyclin-dependent kinase 9 (CDK9) stimulates oncogenic transcriptional pathways in cancer. Here, we evaluate the activity of an orally bioavailable CDK9 inhibitor, CDKI-73, in prostate cancer, a disease characterized by aberrant activity of multiple transcriptional regulators. CDKI-73 caused inhibition of proliferation and cell death in diverse in vitro models of androgen receptor (AR)-driven and AR-independent models of castration-resistant prostate cancer (CRPC). The activity of CDKI-73 was validated in more clinically-relevant systems, including xenografts, patient-derived tumor explants and aggressive patient-derived CRPC organoids. Mechanistically, CDKI-73 inhibited CDK9-mediated phosphorylation of serine 2 on RNA polymerase II and serine 81 on AR. This resulted in reduced levels of anti-apoptotic factors and suppression of signaling pathways regulated by AR, MYC and BRD4, key drivers of dysregulated transcription in prostate cancer. CDKI-73 synergized with the BRD4 inhibitor AZD5153 in cell lines and organoid models of aggressive AR-driven and AR-independent disease. Collectively, our work provides new insights into CDK9’s oncogenic activity and reveals CDKI-73 as a promising therapeutic agent for prostate cancer, particularly aggressive, therapy-resistant subtypes.
2023-10-10 | GSE244716 | GEO
Project description:Cyclin-dependent kinase 9 (CDK9) stimulates oncogenic transcriptional pathways in cancer. Here, we evaluate the activity of an orally bioavailable CDK9 inhibitor, CDKI-73, in prostate cancer, a disease characterized by aberrant activity of multiple transcriptional regulators. CDKI-73 caused inhibition of proliferation and cell death in diverse in vitro models of androgen receptor (AR)-driven and AR-independent models of castration-resistant prostate cancer (CRPC). The activity of CDKI-73 was validated in more clinically-relevant systems, including xenografts, patient-derived tumor explants and aggressive patient-derived CRPC organoids. Mechanistically, CDKI-73 inhibited CDK9-mediated phosphorylation of serine 2 on RNA polymerase II and serine 81 on AR. This resulted in reduced levels of anti-apoptotic factors and suppression of signaling pathways regulated by AR, MYC and BRD4, key drivers of dysregulated transcription in prostate cancer. CDKI-73 synergized with the BRD4 inhibitor AZD5153 in cell lines and organoid models of aggressive AR-driven and AR-independent disease. Collectively, our work provides new insights into CDK9’s oncogenic activity and reveals CDKI-73 as a promising therapeutic agent for prostate cancer, particularly aggressive, therapy-resistant subtypes.
2024-02-25 | GSE255308 | GEO
Project description:Despite the clinical benefit of androgen-deprivation therapy (ADT), the majority of patients with advanced prostate cancer (PCa) ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we identified thioesterase superfamily member 6 (THEM6) as a marker of ADT resistance in PCa. In patients, THEM6 expression correlates with progressive disease and is associated with poor survival. THEM6 deletion reduces in vivo tumour growth and restores castration sensitivity in orthograft models of CRPC. Mechanistically, THEM6 is located at the endoplasmic reticulum (ER) membrane and controls lipid homeostasis by regulating intracellular levels of ether lipids. As a consequence, THEM6 loss in CRPC cells significantly alters ER function, preventing lipid-mediated induction of ATF4 and reducing de novo sterol biosynthesis. Finally, we show that THEM6 is required for the establishment of the MYC-induced stress response. Thus, similar to PCa, THEM6 loss significantly impairs tumorigenesis in the MYC-dependent subtype of triple negative breast cancer. Altogether our results highlight THEM6 as a novel component of the treatment-induced stress response and a promising target for the treatment of CRPC and MYC-driven cancer.
2021-12-11 | PXD024456 | Pride
Project description:Cyclin-dependent kinase 9 (CDK9) phosphorylates RNA polymerase II to promote productive transcription elongation and the phosphorylation also regulates recruitment of the splicing machinery. Here we show that acute CDK9 inhibition affects splicing of thousands of mRNAs. CDK9 inhibition impairs global splicing and there is no evidence for a coordinated response between alternative splicing and the overall transcriptome. Alternative splicing is feature of aggressive prostate cancer (CRPC) and enables generation of an anti-androgen resistant version of a ligand-independent androgen receptor, AR-v7. We show that CDK9 inhibition compromises splicing of the androgen receptor (AR) mRNA due to the faulty utilization of alternative 3’splice site and introduction of premature stop codon. Consequently, this defective splicing results in the loss of AR and AR-v7 expression in models of CRPC. We show that CDK9 expression increases as PC cells develop CRPC-phenotype both in vitro and also in patient samples.
2022-01-10 | GSE169090 | GEO
Project description:The rewiring of transcriptional and epigenetic programs is a hallmark of cancer and a targetable vulnerability for treating metastatic cancers. CDK9, whose primary function is to promote transcriptional elongation at active gene promoters, is emerging as a therapeutic target with broad efficacy in various cancer types. We used the novel and selective CDK9 inhibitor PRT2527 to demonstrate this approach's therapeutic efficacy and tolerability in multiple preclinical tumor models with specific transcriptional dependencies. In castration-resistant prostate cancer (CRPC), PRT2527 inhibited CDK9, AR and other transcription factors (e.g., c-MYC, STAT3, and NF-kB) implicated in disease progression and treatment resistance. PRT2527 reduced the proliferation of tumor cell lines and the growth of 3D tumor organoids and spheroids, demonstrating the impact on the bulk tumor cells and the stem-like subpopulation in human and murine CRPC models. PRT2527 was also highly active in vivo in patient-derived CRPC models LuCaP 35 and LuCap 145.2) and transgenic Pb-Cre4;Ptenflox/flox;R26ERG (ERG/PTEN) mice. Notably, PRT2527 induced relevant changes in gene expression, reflecting the impact on the distinct transcriptional programs of various CRPC models. Despite this heterogeneity, a common core of genes and pathways related to oncogenesis was affected in all models. Our data further demonstrate the efficacy and safety of CDK9 inhibition in multiple models of transcriptionally addicted solid tumors. Given its role in transcription, CDK9 is an ideal target for developing novel therapeutic strategies to block tumor cell plasticity driving tumor progression, metastatic spread, and treatment resistance.
2026-06-04 | E-MTAB-12991 | biostudies-arrayexpress
Project description:The rewiring of transcriptional and epigenetic programs is a hallmark of cancer and a targetable vulnerability for treating metastatic cancers. CDK9, whose primary function is to promote transcriptional elongation at active gene promoters, is emerging as a therapeutic target with broad efficacy in various cancer types. We used the novel and selective CDK9 inhibitor PRT2527 to demonstrate this approach's therapeutic efficacy and tolerability in multiple preclinical tumor models with specific transcriptional dependencies. In castration-resistant prostate cancer (CRPC), PRT2527 inhibited CDK9, AR and other transcription factors (e.g., c-MYC, STAT3, and NF-B) implicated in disease progression and treatment resistance. PRT2527 reduced the proliferation of tumor cell lines and the growth of 3D tumor organoids and spheroids, demonstrating the impact on the bulk tumor cells and the stem-like subpopulation in human and murine CRPC models. PRT2527 was also highly active in vivo in patient-derived CRPC models LuCaP 35 and LuCap 145.2) and transgenic Pb-Cre4;Ptenflox/flox;R26ERG (ERG/PTEN) mice. Notably, PRT2527 induced relevant changes in gene expression, reflecting the impact on the distinct transcriptional programs of various CRPC models. Despite this heterogeneity, a common core of genes and pathways related to oncogenesis was affected in all models. Our data further demonstrate the efficacy and safety of CDK9 inhibition in multiple models of transcriptionally addicted solid tumors. Given its role in transcription, CDK9 is an ideal target for developing novel therapeutic strategies to block tumor cell plasticity driving tumor progression, metastatic spread, and treatment resistance.
2026-06-04 | E-MTAB-12987 | biostudies-arrayexpress
Project description:The rewiring of transcriptional and epigenetic programs is a hallmark of cancer and a targetable vulnerability for treating metastatic cancers. CDK9, whose primary function is to promote transcriptional elongation at active gene promoters, is emerging as a therapeutic target with broad efficacy in various cancer types. We used the novel and selective CDK9 inhibitor PRT2527 to demonstrate this approach's therapeutic efficacy and tolerability in multiple preclinical tumor models with specific transcriptional dependencies. In castration-resistant prostate cancer (CRPC), PRT2527 inhibited CDK9, AR and other transcription factors (e.g., c-MYC, STAT3, and NF-B) implicated in disease progression and treatment resistance. PRT2527 reduced the proliferation of tumor cell lines and the growth of 3D tumor organoids and spheroids, demonstrating the impact on the bulk tumor cells and the stem-like subpopulation in human and murine CRPC models. PRT2527 was also highly active in vivo in patient-derived CRPC models LuCaP 35 and LuCap 145.2) and transgenic Pb-Cre4;Ptenflox/flox;R26ERG (ERG/PTEN) mice. Notably, PRT2527 induced relevant changes in gene expression, reflecting the impact on the distinct transcriptional programs of various CRPC models. Despite this heterogeneity, a common core of genes and pathways related to oncogenesis was affected in all models. Our data further demonstrate the efficacy and safety of CDK9 inhibition in multiple models of transcriptionally addicted solid tumors. Given its role in transcription, CDK9 is an ideal target for developing novel therapeutic strategies to block tumor cell plasticity driving tumor progression, metastatic spread, and treatment resistance.
2026-04-08 | E-MTAB-12986 | biostudies-arrayexpress
Project description:The switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex becomes frequently deregulated in advanced castration-resistant prostate cancer (CRPC). Proteolysis targeting chimera (PROTAC) therapies degrading SWI/SNF ATPases offer a novel approach to interfere with androgen receptor (AR) signaling in AR-dependent castration-resistant prostate cancer (CRPC-AR). To explore the utility of SWI/SNF therapy beyond AR-sensitive CRPC, we investigated SWI/SNF-targeting agents in AR-negative CRPC. SWI/SNF targeting PROTAC treatment of cell lines and organoid models reduced the viability of not only CRPC-AR but also WNT-signaling dependent AR-negative CRPC (CRPC-WNT). We discovered that SWI/SNF ATPase SMARCA4 depletion interfered with the WNT master transcriptional regulator TCF7L2 (TCF4) in CRPC-WNT.
2025-12-16 | GSE313838 | GEO