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Therapeutic efficacy of CDK7 inhibition in pancreatic cancer through proliferation arrest and inducing replication stress [PDX]

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with few effective therapies. Here, we demonstrate that cyclin dependent kinase 7 (CDK7) is essential for the proliferation and viability of PDAC cells by showing potent anti-tumor efficacy for the CDK7-specific inhibitor YKL-5-124 in preclinical PDAC models. Selective CDK7 inhibition leads to G2/M cell cycle arrest and apoptosis in PDAC, while mediating a more modest transcriptional response compared with multi-targeted CDK7/12/13 inhibitors. YKL-5-124 treatment impairs DNA damage repair (DDR) pathways in PDAC cells and evokes genomic instability by inducing R-loop formation and DNA replication stress in telomeric regions leading to chromosomal bridging and micronuclei formation. Furthermore, we demonstrate that selective CDK7 inhibition has in vitro and in vivo combinatorial efficacy with gemcitabine chemotherapy through pronounced induction of replication stress and apoptosis. Collectively, these findings support selective CDK7 inhibition as a promising therapeutic strategy for PDAC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE270206 | GEO | 2026/01/01

REPOSITORIES: GEO

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Therapeutic efficacy of CDK7 inhibition in pancreatic cancer through proliferation arrest and inducing replication stress [8898T]

Project description:Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with few effective therapies. Here, we demonstrate that cyclin dependent kinase 7 (CDK7) is essential for the proliferation and viability of PDAC cells by showing potent anti-tumor efficacy for the CDK7-specific inhibitor YKL-5-124 in preclinical PDAC models. Selective CDK7 inhibition leads to G2/M cell cycle arrest and apoptosis in PDAC, while mediating a more modest transcriptional response compared with multi-targeted CDK7/12/13 inhibitors. YKL-5-124 treatment impairs DNA damage repair (DDR) pathways in PDAC cells and evokes genomic instability by inducing R-loop formation and DNA replication stress in telomeric regions leading to chromosomal bridging and micronuclei formation. Furthermore, we demonstrate that selective CDK7 inhibition has in vitro and in vivo combinatorial efficacy with gemcitabine chemotherapy through pronounced induction of replication stress and apoptosis. Collectively, these findings support selective CDK7 inhibition as a promising therapeutic strategy for PDAC.

2026-01-01 | GSE270204 | GEO

CDK7 controls E2F- and MYC-driven proliferative and metabolic vulnerabilities in multiple myeloma

Project description:Therapeutic targeting of CDK7 has proven beneficial in pre-clinical studies, yet the off-target effects of currently available CDK7 inhibitors make it difficult to pinpoint the exact mechanisms behind MM cell death mediated by CDK7 inhibition. Here, we show that CDK7 expression positively correlates with E2F and MYC transcriptional programs in multiple myeloma (MM) patient cells; and its selective targeting counteracts E2F activity via perturbation of the CDKs/Rb axis and impairs MYC-regulated metabolic gene signatures translating into defects in glycolysis and reduced levels of lactate production in MM cells. CDK7 inhibition using the covalent small molecule inhibitor YKL-5-124 elicits a strong therapeutic response with minimal effects on normal cells, and causes in vivo tumor regression increasing survival in several MM mouse models including a genetically engineered mouse model of MYC-dependent MM. Through its role as a critical cofactor and regulator of MYC and E2F activity, CDK7 is therefore a master regulator of oncogenic cellular programs supporting MM growth and survival, and a valuable therapeutic target providing rationale for development of YKL-5-124 for clinical use.

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CDK7-targeted therapy effectively disrupts cell cycle progression and oncogenic signaling in head and neck squamous cell carcinoma. [PDX]

Project description:Head and neck squamous cell carcinoma (HNSCC) remains a prevalent and aggressive malignancy, characterized by a lack of targeted therapies and limited clinical benefits. Here, we conducted an optimized whole-genome CRISPR screen across five HNSCC cell lines aimed at identifying actionable genetic vulnerabilities for rapid preclinical evaluation as novel targeted therapies. Given their critical role in cancer, cyclin-dependent kinases (CDKs) were prioritized for further investigation. Among these, CDK7 was identified as an essential and targetable gene across all five cell lines, prompting its selection for in-depth functional and molecular characterization. Genetic and pharmacological inhibition of CDK7 significantly and consistently reduced tumor cell proliferation due to generalized cell cycle arrest and apoptosis induction. Additionally, CDK7 knockout (KO) and selective inhibitors (YKL-5-124 and samuraciclib) demonstrated potent antitumor activity, effectively suppressing tumor growth in HNSCC patient-derived organoids (PDOs), as well as in both cell line- and patient-derived xenograft (PDX) mouse models with minimal toxicity. Mechanistically, CDK7 inhibition led to a broad downregulation of gene sets related to cell cycle progression and DNA repair, and significantly reduced the transcription of essential genes and untargetable vulnerabilities identified by our CRISPR screen. These findings highlight CDK7 as a promising therapeutic target for HNSCC. Our study provides strong evidence of the robust antitumor activity of CDK7-selective inhibition in disease-relevant preclinical models, strongly supporting its progression to clinical testing.

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CDK7-targeted therapy effectively disrupts cell cycle progression and oncogenic signaling in head and neck cancer

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CDK7 inhibition interdicts deregulated transcription and cell cycle control in multiple myeloma [Resistant_MM_Cell_Lines_6Hr_RNA-seq]

Project description:Cyclin dependent kinases (CDKs) are high value therapeutical targets owing to their important roles in regulating transcription and the cell cycle — two pathways commonly altered in cancer and especially in multiple myeloma (MM). Among CDKs, CDK7 uniquely bridges cell cycle and transcriptional control by activating other cell cycle CDKs and forming the general transcription factor TFIIH. Utilizing a recently developed highly selective covalent inhibitor of CDK7, we demonstrate that CDK7 inhibition elicits a strong therapeutic response in MM blocking proliferation in vitro and driving tumor regression and prolonged survival in vivo. CDK7 inhibition counteracts molecular hallmarks of deregulated cell cycle control at the G1/S checkpoint. Additionally, we show CDK7 inhibition selectively downregulates oncogenic E2F and cell cycle gene expression programs. Combination treatment with JQ1 which target oncogenic enhancer driven gene expression programs proved highly synergistic. These results support CDK7 as an attractive and therapeutically actionable molecular vulnerability in MM. Cell count normalized RNA-seq in Resistant MM cell lines (XG1 and AMO1; 18 total samples; 3 technical replicates) upon treatment with the selective covalent CDK7 inhibitor YKL-5-124 Mariateresa,Fulciniti Nikhil,Munshi

2022-04-01 | GSE172442 | GEO

CDK7 inhibition interdicts deregulated transcription and cell cycle control in multiple myeloma [Sensitive_MM_Cell_Lines_RNA-seq]

Project description:Cyclin dependent kinases (CDKs) are high value therapeutical targets owing to their important roles in regulating transcription and the cell cycle — two pathways commonly altered in cancer and especially in multiple myeloma (MM). Among CDKs, CDK7 uniquely bridges cell cycle and transcriptional control by activating other cell cycle CDKs and forming the general transcription factor TFIIH. Utilizing a recently developed highly selective covalent inhibitor of CDK7, we demonstrate that CDK7 inhibition elicits a strong therapeutic response in MM blocking proliferation in vitro and driving tumor regression and prolonged survival in vivo. CDK7 inhibition counteracts molecular hallmarks of deregulated cell cycle control at the G1/S checkpoint. Additionally, we show CDK7 inhibition selectively downregulates oncogenic E2F and cell cycle gene expression programs. Combination treatment with JQ1 which target oncogenic enhancer driven gene expression programs proved highly synergistic. These results support CDK7 as an attractive and therapeutically actionable molecular vulnerability in MM. Cell count normalized RNA-seq in Sensitive MM cell lines (H929 and MM1S; 24 total samples; 3 technical replicates) upon treatment with the selective covalent CDK7 inhibitor YKL-5-124 Mariateresa,Fulciniti Nikhil,Munshi

2022-04-01 | GSE172444 | GEO

CDK7 inhibition interdicts deregulated transcription and cell cycle control in multiple myeloma [Resistant_MM_Cell_Lines_24Hr_RNA-seq]

2022-04-01 | GSE172443 | GEO

Activation of the p53 transcriptional program sensitizes cancer cells to Cdk7 inhibitors

Project description:Cdk7, the CDK-activating kinase and transcription factor IIH component, is a target of inhibitors that kill cancer cells by exploiting tumor-specific transcriptional dependencies. However, whereas selective inhibition of analog-sensitive (AS) Cdk7 in colon cancer derived cells arrests division and disrupts transcription, it does not by itself trigger apoptosis efficiently. Here we show that p53 activation by 5-fluorouracil or nutlin-3 synergizes with a reversible Cdk7as inhibitor to induce cell death. Synthetic lethality was recapitulated with covalent inhibitors of wild-type Cdk7, THZ1 or the more selective YKL-1-116. The effects were allele-specific; a CDK7as mutation conferred both sensitivity to bulky adenine analogs and resistance to covalent inhibitors. Non-transformed colon epithelial cells were resistant to these combinations, as were cancer-derived cells with p53-inactivating mutations. Apoptosis was dependent on death receptor DR5, a p53 transcriptional target whose expression was refractory to Cdk7 inhibition. Therefore, p53 activation induces transcriptional dependency to sensitize cancer cells to Cdk7 inhibition.

2017-10-10 | GSE99794 | GEO

Transcriptional CDK inhibitors as potential treatment option for testicular germ cell tumors

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

Loss of function of CDK7 is Synthetically Lethal with Fatty Acid Oxidation Inhibition in Glioblastoma

Project description:CDK7 has been identified as a potential drug target for glioblastoma (GBM), a highly lethal primary brain tumor. However, resistance to therapy develops quickly, which may be facilitated by drug-induced reprogramming of metabolism. By combination of a transcriptome and metabolite screening analyses followed by carbon tracing (U-13C-Glucose, U-13C-Glutamine and U-13C-Palmitic acid) and extracellular flux analysis, we demonstrated that both genetic and pharmacological (YKL-5-124 and THZ1) CDK7 inhibition elicited substantial metabolic reprogramming. Specifically, CDK7 inhibition elicited an increase of oxygen consumption rate fueled by enhanced fatty acid oxidation (FAO) manifested by enhanced labeling of citric acid cycle intermediates from palmitic acid. Consistently, the combination treatment of CDK7 inhibitors with blockers of FAO (etomoxir) exerted substantial synergistic growth inhibition in patient derived xenograft as well as neurosphere GBM cultures, which was mainly driven by a collapse of oxidative energy metabolism. In turn, exogenous administration of adenosine triphosphate partially rescued from the cell death induced by the combination treatment. Finally, the combined administration of YKL-5-124 and etomoxir extended overall in an orthotopic patient-derived xenograft model of GBM. In summary, these data support that simultaneous targeting of CDK7 and FAO might be a potential novel therapy against GBM.

2023-09-01 | GSE229967 | GEO

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