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.
Athanasios R Paliouras   #  1  2 ,  Marta Buzzetti   #  1  3 ,  Lei Shi   #  1  2 ,  Ian J Donaldson  4 ,  Peter Magee  1  2 ,  Sudhakar Sahoo  5 ,  Hui-Sun Leong  5 ,  Matteo Fassan  6 ,  Matthew Carter  2  7 ,  Gianpiero Di Leva  8 ,  Matthew G Krebs  2  7 ,  Fiona Blackhall  2  7 ,  Christine M Lovly  9 ,  Michela Garofalo  1  2
Affiliations
  • 1. Transcriptional Networks in Lung Cancer Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
  • 2. Cancer Research UK Lung Cancer Centre of Excellence, Manchester and University College London, London, UK.
  • 3. Biomedical Research Centre, School of Science, Engineering and Environment, University of Salford, Salford, UK.
  • 4. Bioinformatics Core Facility, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
  • 5. Computational Biology Support, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
  • 6. Department of Medicine, Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy.
  • 7. Division of Cancer Sciences, Faculty of Biology, Medicine and Health, Christie Hospital, University of Manchester, Manchester, UK.
  • 8. School of Pharmacy and Bioengineering, Guy Hilton Research Institute, Keele University, Keele, UK.
  • 9. Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
  • # Contributed equally.
PMID: 32558295 DOI: 10.15252/emmm.201911099
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.
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