CDK7 is a prognostic biomarker for non-small cell lung cancer

Kuempers, Christiane; Jagomast, Tobias; Heidel, Carsten; Paulsen, F.; Bohnet, Sabine; Schierholz, Stefanie; Dreyer, Eva; Kirfel, Jutta; Perner, Sven

doi:10.3389/fonc.2022.927140

Cited by 2 publications

(1 citation statement)

References 21 publications

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“…Additionally, the CAK complex is a key component of the transcription factor TFIIH involved in transcription initiation and elongation (14). CDK7 is aberrantly overexpressed in different types of cancer (15)(16)(17) and signi cant progress has been made in the development of selective CDK7 inhibitors, which have shown e cacy preclinically in multiple tumor types including breast (18, 19), pancreatic (20), and lung cancer (21) among others.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide functional CRISPR screen reveals CDK7 as a targetable therapeutic vulnerability for head and neck cancer

Otero-Rosales,

Álvarez-González,

de Luxán-Delgado

et al. 2024

Preprint

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Background: Head and neck squamous cell carcinoma (HNSCC) remains a challenging prevalent lethal malignancy, with still scarce targeted therapies and rather limited clinical benefit. We conducted an optimized genome-wide functional CRISPR screen aimed at identifying actionable genetic vulnerabilities for rapid preclinical evaluation as novel targeted therapies. Cyclin-dependent kinases (CDKs) were prioritized as pivotal in cancer therapy. Methods: Whole-genome CRISPR KO screen was performed in a panel of five HNSCC cell lines. CDK7 was selected for further functional and molecular characterization. The effects of CRISPR CDK7 knockout (KO) and CDK7-selective inhibitors were thoroughly investigated in cellular models using viability, colony formation and apoptosis assays, cell cycle analysis, and global transcriptomics by RNAseq. CDK7 inhibition was also therapeutically evaluated in mouse xenografts and patient-derived organoids (PDOs). Results: CDK7 was identified as an essential gene across all five HNSCC cell lines screened. Genetic and pharmacological CDK7 inhibition significantly and consistently reduced tumor cell proliferation due to generalized cell cycle arrest and apoptosis induction. CDK7 KO, YKL-5-124 and samuraciclib also showed a potent antitumor activity effectively abrogating tumor growth in HNSCC PDOs and also in mouse xenograft models without significant toxicity. Mechanistically, CDK7 inhibition led to a broad downregulation of gene sets for cell cycle progression, DNA repair, and massively reduced the transcription of several essential genes and untargetable vulnerabilities identified by our CRISPR screen. Conclusions: CDK7 emerges as a promising targetable therapeutic vulnerability for HNSCC. Our study provides broad-based evidence for the robust antitumor activity of CDK7-selective inhibitors in disease-relevant preclinical models, strongly supporting patient testing.

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Section: Introductionmentioning

confidence: 99%

Genome-wide functional CRISPR screen reveals CDK7 as a targetable therapeutic vulnerability for head and neck cancer

Otero-Rosales,

Álvarez-González,

de Luxán-Delgado

et al. 2024

Preprint

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Adenovirus vaccine targeting kinases induces potent antitumor immunity in solid tumors

Zhu,

Lu,

Tang

et al. 2024

J Immunother Cancer

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BackgroundTargeting kinases presents a potential strategy for treating solid tumors; however, the therapeutic potential of vaccines targeting kinases remains uncertain.MethodsAdenovirus (Ad) vaccines encoding Aurora kinase A (AURKA) or cyclin-dependent kinase 7 (CDK7) were developed, and their therapeutic potentials were investigated by various methods including western blot, flow cytometry, cytotoxic T lymphocyte assay, and enzyme-linked immunospot (ELISpot), in mouse and humanized solid tumor models.ResultsCo-immunization with Ad-AURKA/CDK7 effectively prevented subcutaneous tumor growth in the Renca, RM-1, MC38, and Hepa1-6 tumor models. In therapeutic tumor models, Ad-AURKA/CDK7 treatment impeded tumor growth and increased immune cell infiltration. Administration of Ad-AURKA/CDK7 promoted the induction and maturation of dendritic cell subsets and augmented multifunctional CD8+T-cell antitumor immunity. Furthermore, the vaccine induced a long-lasting antitumor effect by promoting the generation of memory CD8+T cells. Tumor recovery on CD8+T-cell depletion underscored the indispensable role of these cells in the observed therapeutic effects. The potent efficacy of the Ad-AURKA/CDK7 vaccine was consistently demonstrated in lung metastasis, orthotopic, and humanized tumor models by inducing multifunctional CD8+T-cell antitumor immune responses.ConclusionsOur findings illustrate that the Ad-AURKA/CDK7 vaccine targeting dual kinases AURKA and CDK7 emerges as a promising and effective therapeutic approach for the treatment of solid tumors.

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CDK7 is a prognostic biomarker for non-small cell lung cancer

Cited by 2 publications

References 21 publications

Genome-wide functional CRISPR screen reveals CDK7 as a targetable therapeutic vulnerability for head and neck cancer

Genome-wide functional CRISPR screen reveals CDK7 as a targetable therapeutic vulnerability for head and neck cancer

Adenovirus vaccine targeting kinases induces potent antitumor immunity in solid tumors

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