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 propose a new treatment strategy for a subset of patients with acquired resistance to first-, second- and third-generation ALK inhibitors. READ ARTICLE
EMBO Molecular Medicine DOI:10.15252/emmm.201911099
Authors: Athanasios R Paliouras, Marta Buzzetti, Lei Shi, Ian J Donaldson, Peter Magee, Sudhakar Sahoo, Hui-Sun Leong, Matteo Fassan, Matthew Carter, Gianpiero Di Leva, Matthew G Krebs, Fiona Blackhall, Christine M Lovly, Michela Garofalo