Vulnerability of drug-resistant EML4-ALK rearranged lung cancer to transcriptional inhibition

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

SUBMITTER: Mr. Athanasios Rafail Paliouras 

PROVIDER: S-SCDT-EMM-2019-11099P | biostudies-other |

REPOSITORIES: biostudies-other