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

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    Authors
    Paliouras, Athanasios R
    Buzzetti, M
    Shi, Lei
    Donaldson, IJ
    Magee, Peter
    Sahoo, Sudhakar
    Leong, Hui Sun
    Fassan, M
    Carter, Mathew
    Di Leva, G
    Krebs, Matthew G
    Blackhall, Fiona H
    Lovly, CM
    Garofalo, Michela
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    Affiliation
    Transcriptional Networks in Lung Cancer Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
    Issue Date
    2020
    
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    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.
    Citation
    Paliouras 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.
    Journal
    EMBO Molecular Medicine
    URI
    http://hdl.handle.net/10541/623065
    DOI
    10.15252/emmm.201911099
    PubMed ID
    32558295
    Additional Links
    https://dx.doi.org/10.15252/emmm.201911099
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.15252/emmm.201911099
    Scopus Count
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