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

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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Publication Details

Journal
Signal Transduction and Targeted Therapy
Published
2025-11-05
DOI
https://doi.org/10.1038/s41392-025-02452-z
Citations
2
Primary Topic
Cancer-related Molecular Pathways
Type
article
Field-Weighted Citation Impact
2.09

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article

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

Konstantinos Tzelepis, Juan Pablo Rodrigo, Ivan Fernández‐Vega, Irene Ferrer et al.
2 citations
Signal Transduction and Targeted Therapy
Cancer-related Molecular Pathways
2.09
article

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

Konstantinos Tzelepis, Juan Pablo Rodrigo, Ivan Fernández‐Vega, Irene Ferrer, Isabel Pazos, George S. Vassiliou, Corina Lorz, María D. Corte‐Torres, Saúl Álvarez–Teijeiro, Beatriz de Luxán‐Delgado, Francisco Hermida‐Prado, Ramón Garcı́a-Escudero, María Otero‐Rosales, Sonia Del Marro, Rocío Granda‐Díaz, Esperanza Pozo-Agundo, Mónica Álvarez‐Fernández, Juana Maria Garcia-Pedrero, Mar Rodríguez-Santamaría, Miguel Álvarez-González, Ana López-Fernández
article en
2 citations

Abstract

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.

Signal Transduction and Targeted TherapyVol. 10(1)
Universidad de Oviedo (ES), Wellcome/MRC Cambridge Stem Cell Institute (GB), University of Cambridge (GB), Instituto de Salud Carlos III (ES), Wellcome Sanger Institute (GB), Research Institute Hospital 12 de Octubre (ES), Hospital Universitario Central de Asturias (ES), Centro de Investigación del Cáncer (ES), Medical Research Network (US), Instituto de Investigación Sanitaria del Principado de Asturias (ES)
Wellcome Trust, Gobierno del Principado de Asturias, UK Research and Innovation, Ministerio de Ciencia, Innovación y Universidades, Leukaemia UK, European Commission, Universidad de Oviedo, Centro de Investigación Biomédica en Red de Cáncer, Instituto de Investigación Sanitaria del Principado de Asturias, Medical Research Council, Instituto de Salud Carlos III, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, Agencia Estatal de Investigación
Openalex Percentile: Top 10%
Cancer-related Molecular Pathways
2.09
DOIOpen Access PDFOpenAlex
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