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

Paliouras, Athanasios R; Buzzetti, Marta; Shi, Lei; Donaldson, Ian J; Magee, Peter; Sahoo, Sudhakar; Leong, Hui-Sun; Fassan, Matteo; Carter, Matthew; Di Leva, Gianpiero; Krebs, Matthew G; Blackhall, Fiona; Lovly, Christine M; Garofalo, Michela

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 propose a new treatment strategy for a subset of patients with acquired resistance to first-, second- and third-generation ALK inhibitors.

Citation

Paliouras, A. R., Buzzetti, M., Shi, L., Donaldson, I. J., Magee, P., Sahoo, S., …Garofalo, M. (2020). Vulnerability of drug-resistant EML4-ALK rearranged lung cancer to transcriptional inhibition. EMBO Molecular Medicine, 12(7), Article e11099. https://doi.org/10.15252/emmm.201911099

• Journal Article Type: Article
• Acceptance Date: May 21, 2020
• Publication Date: Jun 17, 2020
• Journal: EMBO Molecular Medicine
• Print ISSN: 1757-4676
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 12
• Issue: 7
• Article Number: e11099
• DOI: https://doi.org/10.15252/emmm.201911099
• Keywords: ALK; EML4 translocation; ALKi; CDKi; drug resistance; NSCLC
• Publisher URL: https://doi.org/10.15252/emmm.201911099