Vulnerability of drug-resistant EML4-ALK rearranged lung cancer to transcriptional inhibition
AuthorsPaliouras, Athanasios R
Leong, Hui Sun
Di Leva, G
Krebs, Matthew G
Blackhall, Fiona H
AffiliationTranscriptional Networks in Lung Cancer Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
MetadataShow full item record
AbstractA 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.
CitationPaliouras AR, Buzzetti M, Shi L, Donaldson IJ, Magee P, Sahoo S, et al. Vulnerability of drug-resistant EML4-ALK rearranged lung cancer to transcriptional inhibition. EMBO Mol Med. 2020;12(7):e11099.
JournalEMBO Molecular Medicine
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