CDK7-targeted therapy effectively disrupts cell cycle progression and oncogenic signaling in head and neck cancer
Year: 2025
Type: article
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.
Authors: 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
Institutions: Universidad de Oviedo, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Cáncer, Instituto de Investigación Sanitaria del Principado de Asturias, Research Institute Hospital 12 de Octubre, Spanish National Cancer Research Centre, Hospital Universitario 12 De Octubre, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, Hospital Universitario Central de Asturias, Wellcome/MRC Cambridge Stem Cell Institute, University of Cambridge, Wellcome Sanger Institute, Consejo Superior de Investigaciones Científicas, Universidad de Salamanca, Centro de Investigación del Cáncer
Language: English
Topic: Head and Neck Cancer Studies
Subfield: Otorhinolaryngology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,790
Funders: Wellcome Trust, Gobierno del Principado de Asturias, UK Research and Innovation, Ministerio de Ciencia, Innovación y Universidades, Leukaemia UK, European Commission, Ministerio de Economía y Competitividad, 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
Awards: G1307865877, G1452742953, G1474699163, G1556225826, G1605422331, G1702534363, Interacciones del tumor y su microambiente como fuente de nuevos biomarcadores y dianas terapéuticas para el diagnóstico y manejo clínico de pacientes con cáncer de cabeza y cuello, G2110239192, G2128682156, Desentrañando la heterogeneidad y plasticidad funcional de los fibroblastos asociados a cáncer para mejorar el tratamiento personalizado de los tumores de cabeza y cuello, G2262748287, G2542987457, G2834502797, G300979063, G324521453, G3480869486, G3534073423, G4042783231, G4126969020, G4197288519, G425668148, G446611021, G4473036618, G464301484, G4650691966, G4774041930, G4862370562, G4927655261, G4974690386, G5055832054, G5080475149, G5213524516, G5273193153, G5485603675, G5499292921, G5523723118, G5635532810, TERAPIA PERSONALIZADA DE NUEVA GENERACION CON ANTICUERPOS INMUNOESTIMULADORES E INHIBIDORES DE PUNTOS DE CONTROL INMUNE EN CANCER, G5780737631, G6102325852, G6603613172, BIOPSIA LIQUIDA EN CANCER DE CABEZA Y CUELLO, G6731524417, G677677376, G6874468849, G6901063589, G7081990640, G7170258134, G7213434345, G7245979228, G7333567696, G7401793180, G7557550218, G763088774, G7658215705, G7805626310, G7851274461, G7924536169, G8277039178, G8281166263, G8322090566, G8485703158, G8497050386
OpenAlex ID: W4415992125