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

EMBO Mol Med. 2020 Jul 7;12(7):e11099. doi: 10.15252/emmm.201911099. Epub 2020 Jun 17.

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.

Keywords: ALK/EML4 translocation; ALKi; CDKi; NSCLC; drug resistance.

Publication types

  • Research Support, Non-U.S. Gov't