Journal Article

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

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

2025

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 692/4028/67/1059 / 692/4028/67/1536 / Animal models / Animals / Antitumor activity / Apoptosis / Cancer Research / Cancer therapies / Cell Biology / Cell cycle / Cell Cycle - drug effects / Cell growth / Cell Line, Tumor / Cell proliferation / Cell Proliferation - drug effects / CRISPR / Cyclin-Dependent Kinase-Activating Kinase / Cyclin-dependent kinases / Cyclin-Dependent Kinases - antagonists & inhibitors / Cyclin-Dependent Kinases - genetics / Data analysis / DNA repair / Gene amplification / Genomes / Head & neck cancer / Head and neck carcinoma / Head and Neck Neoplasms - drug therapy / Head and Neck Neoplasms - genetics / Head and Neck Neoplasms - pathology / Humans / Internal Medicine / Kinases / Malignancy / Medical prognosis / Medicine / Medicine & Public Health / Mice / Molecular Targeted Therapy / Oncology / Organoids / Pathology / Proteins / Signal Transduction - drug effects / Signal Transduction - genetics / Squamous cell carcinoma / Squamous Cell Carcinoma of Head and Neck - drug therapy / Squamous Cell Carcinoma of Head and Neck - genetics / Squamous Cell Carcinoma of Head and Neck - pathology / Therapeutic targets / Toxicity / Tumors / Xenograft Model Antitumor Assays