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

Di Leva

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.

• Acceptance Date: May 21, 2020
• Publication Date: Jun 17, 2020
• Journal: EMBO Molecular Medicine
• Print ISSN: 1757-4676
• Publisher: Wiley
• 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