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

Paliouras, Athanasios R; Buzzetti, Marta; Shi, Lei; Donaldson, Ian J; Magee, Peter; Sahoo, Sudhakar; Leong, Hui-Sun; Fassan, Matteo; Carter, Matthew; Di Leva, Gianpiero; Krebs, Matthew G; Blackhall, Fiona; Lovly, Christine M; Garofalo, Michela

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


Authors

Athanasios R Paliouras

Marta Buzzetti

Lei Shi

Ian J Donaldson

Peter Magee

Sudhakar Sahoo

Hui-Sun Leong

Matteo Fassan

Matthew Carter

Matthew G Krebs

Fiona Blackhall

Christine M Lovly

Michela Garofalo



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.

Journal Article Type Article
Acceptance Date May 21, 2020
Publication Date Jun 17, 2020
Journal EMBO Molecular Medicine
Print ISSN 1757-4676
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 12
Issue 7
Article Number e11099
DOI https://doi.org/10.15252/emmm.201911099
Keywords ALK; EML4 translocation; ALKi; CDKi; drug resistance; NSCLC
Publisher URL https://doi.org/10.15252/emmm.201911099

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