{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Paliouras AR"],"funding":["Cancer Research UK"],"pagination":["e11099"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC7338803"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["12(7)"],"pubmed_abstract":["A subset of lung adenocarcinomas is driven by the EML4-ALK translocation. Even though ALK inhibitors in the clinic lead to excellent initial responses, acquired resistance to these inhibitors due to on-target mutations or parallel pathway alterations is a major clinical challenge. Exploring these mechanisms of resistance, we found that EML4-ALK cells parental or resistant to crizotinib, ceritinib or alectinib are remarkably sensitive to inhibition of CDK7/12 with THZ1 and CDK9 with alvocidib or dinaciclib. These compounds robustly induce apoptosis through transcriptional inhibition and downregulation of anti-apoptotic genes. Importantly, alvocidib reduced tumour progression in xenograft mouse models. In summary, our study takes advantage of the transcriptional addiction hypothesis to propo"],"journal":["EMBO molecular medicine"],"pubmed_title":["Vulnerability of drug-resistant EML4-ALK rearranged lung cancer to transcriptional inhibition."],"pmcid":["PMC7338803"],"funding_grant_id":["29420","C5759/A20971"],"pubmed_authors":["Di Leva G","Shi L","Magee P","Paliouras AR","Leong HS","Buzzetti M","Blackhall F","Donaldson IJ","Sahoo S","Lovly CM","Krebs MG","Fassan M","Garofalo M","Carter M"],"additional_accession":[]},"is_claimable":false,"name":"Vulnerability of drug-resistant EML4-ALK rearranged lung cancer to transcriptional inhibition.","description":"A subset of lung adenocarcinomas is driven by the EML4-ALK translocation. Even though ALK inhibitors in the clinic lead to excellent initial responses, acquired resistance to these inhibitors due to on-target mutations or parallel pathway alterations is a major clinical challenge. Exploring these mechanisms of resistance, we found that EML4-ALK cells parental or resistant to crizotinib, ceritinib or alectinib are remarkably sensitive to inhibition of CDK7/12 with THZ1 and CDK9 with alvocidib or dinaciclib. These compounds robustly induce apoptosis through transcriptional inhibition and downregulation of anti-apoptotic genes. Importantly, alvocidib reduced tumour progression in xenograft mouse models. In summary, our study takes advantage of the transcriptional addiction hypothesis to propo","dates":{"release":"2020-01-01T00:00:00Z","publication":"2020 Jul","modification":"2025-05-29T19:52:36.781Z","creation":"2025-05-29T19:52:36.781Z"},"accession":"S-EPMC7338803","cross_references":{"pubmed":["32558295"],"doi":["10.15252/emmm.201911099"]}}