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 ...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.展开更多
基金supported by the Instituto de Salud Carlos III(ISCIII)through the project grants PI19/00560,PI21/00208,PI22/00167,PI24/00398,PMPTA22/00167 and CIBERONC(CB16/12/00390,CB16/12/00228,and CB16/12/00442)co-funded by the European Union,the Instituto de Investigación Sanitaria del Principado de Asturias(ISPA),Fundación Bancaria CajasturIUOPA,and Universidad de Oviedo.Additional funding was provided through grants PID2020-117236RB-I00 and CNS2023-1444-73+15 种基金funded by MCIU/AEI/10.13039/501100011033 and“European Union Next Generation EU/PRTR”the Scientific Foundation of the Spanish Association against Cancer(LABAE235202ALVA)also funded by the Government of the Principality of Asturias through the Agency for Science,Business Competitiveness and Innovation of the Principality of Asturias and co-financed by the European Union,through the Grants“Subvenciones para Grupos de Investigación de Organismos del Principado de Asturias para el Ejercicio 2024”(IDE/2024/000778)M.O.-R.,I.P.,and E.P.-A are recipients of a PFIS predoctoral fellowship from ISCIII(FI23/00037,FI24/00083 and FI20/00064)S.D.M.is supported by a grant from the Programa de Formación de Profesorado Universitario from the Spanish Ministry of Universities(FPU21/05639)S.A.-T.is a recipient of a Miguel Servet fellowship from ISCIII(CP23/00101)co-funded by the European UnionK.T.is supported by Wellcome Trust(grants RG83195,G106133 and G127005)UKRI Medical Research Council(grant RG83195)Leukaemia UK(grants G108148 and G117699)I.F.is a recipient of a Miguel Servet fellowship from ISCIII(CP21/00052)M.A.F.was supported by the Asociación Española contra el Cáncer(AECC2019/INVES19001ALVA)M.A.G.is a recipient of a Severo Ochoa predoctoral fellowship from the Principado de Asturias(BP21-205)F.H.-P.is a recipient of a Miguel Servet fellowship from ISCIII(CP24/00064)funded by Fundación Alimerka and recipient of a Maria Zambrano postdoctoral fellowship at the University of Oviedo(2022-2024).
文摘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.
