biostudies-literaturePaliouras ARCancer Research UKe11099https://www.ebi.ac.uk/biostudies/studies/S-EPMC7338803biostudies-literatureUnknown12(7)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 propoEMBO molecular medicineVulnerability of drug-resistant EML4-ALK rearranged lung cancer to transcriptional inhibition.PMC733880329420C5759/A20971Di Leva GShi LMagee PPaliouras ARLeong HSBuzzetti MBlackhall FDonaldson IJSahoo SLovly CMKrebs MGFassan MGarofalo MCarter MfalseVulnerability of drug-resistant EML4-ALK rearranged lung cancer to transcriptional inhibition.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 propo2020-01-01T00:00:00Z2020 Jul2025-05-29T19:52:36.781Z2025-05-29T19:52:36.781ZS-EPMC73388033255829510.15252/emmm.201911099