2. Academic Validation
  3. CDK7-targeted therapy effectively disrupts cell cycle progression and oncogenic signaling in head and neck cancer

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

  • Signal Transduct Target Ther. 2025 Nov 6;10(1):363. doi: 10.1038/s41392-025-02452-z.
María Otero-Rosales 1 2 3,  Miguel Álvarez-González 1 2 3,  Irene Pazos 4,  Beatriz de Luxán-Delgado 1 2,  Sonia Del Marro 5 6,  Esperanza Pozo-Agundo 1 2 3,  Mar Rodríguez-Santamaría 1,  Ana López-Fernández 7,  Daniela Corte-Torres 8,  Rocío Granda-Díaz 1 2 3,  Saúl Álvarez-Teijeiro 1 2 3,  Iván Fernández-Vega 8 9,  Corina Lorz 3 5 6,  Ramón García-Escudero 3 5 6,  Juan P Rodrigo 1 2 3 10,  Konstantinos Tzelepis 11 12 13,  George Vassiliou 11 12 14,  Irene Ferrer 3 4,  Mónica Álvarez-Fernández # 1 2 15,  Juana María García-Pedrero # 16 17 18,  Francisco Hermida-Prado # 19 20 21
Affiliations

Affiliations

  • 1 Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain.
  • 2 Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain.
  • 3 Spanish Biomedical Research Network in Cancer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain.
  • 4 Targeted Therapies for Precisión Oncology Group and H12O-CNIO Lung Cancer Clinical Research Unit, Instituto de Investigación Sanitaria 12 de Octubre (imas12), CNIO, Madrid, Spain.
  • 5 Molecular Oncology Unit, CIEMAT, Madrid, Spain.
  • 6 Research Institute 12 de Octubre imas12, University Hospital 12 de Octubre, Madrid, Spain.
  • 7 Molecular Histopathology Unit, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain.
  • 8 Biobank of Principado de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain.
  • 9 Department of Pathology, Hospital Universitario Central de Asturias, Oviedo, Spain.
  • 10 Department of Otolaryngology, Hospital Universitario Central de Asturias, Oviedo, Spain.
  • 11 Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
  • 12 Department of Haematology, University of Cambridge, Cambridge, UK.
  • 13 Milner Therapeutics Institute, University of Cambridge, Cambridge, UK.
  • 14 Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK.
  • 15 Centro de Investigación del Cáncer, CSIC-University of Salamanca, Campus Miguel de Unamuno, Salamanca, Spain.
  • 16 Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain. [email protected].
  • 17 Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain. [email protected].
  • 18 Spanish Biomedical Research Network in Cancer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain. [email protected].
  • 19 Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain. [email protected].
  • 20 Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, Spain. [email protected].
  • 21 Spanish Biomedical Research Network in Cancer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain. [email protected].
  • # Contributed equally.
PMID: 41193441 DOI: 10.1038/s41392-025-02452-z
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.

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