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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月6日

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  • María Otero-Rosales,
  • Miguel Álvarez-González,
  • Irene Pazos,
  • Beatriz de Luxán-Delgado,
  • Sonia Del Marro,
  • Esperanza Pozo-Agundo,
  • Mar Rodríguez-Santamaría,
  • Ana López-Fernández,
  • Daniela Corte-Torres,
  • Rocío Granda-Díaz,
  • Saúl Álvarez-Teijeiro,
  • Iván Fernández-Vega,
  • Corina Lorz,
  • Ramón García-Escudero,
  • Juan P. Rodrigo,
  • Konstantinos Tzelepis,
  • George Vassiliou,
  • Irene Ferrer,
  • Mónica Álvarez-Fernández,
  • Juana María García-Pedrero,
  • Francisco Hermida-Prado

摘要

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.