2. Academic Validation
  3. Vulnerability of drug-resistant EML4-ALK rearranged lung cancer to transcriptional inhibition

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

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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