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, H‐S; Fassan, Matteo; Carter, Matthew; Di Leva, Gianpiero; Krebs, Matthew G; Blackhall, Fiona; Lovly, Christine M; Garofalo, Michela

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
• Online Publication Date: Jun 17, 2020
• Publication Date: Jul 7, 2020
• Deposit Date: Jun 29, 2020
• Publicly Available Date: Jun 29, 2020
• Journal: EMBO Molecular Medicine
• Print ISSN: 1757-4676
• Electronic ISSN: 1757-4684
• Publisher: Wiley
• Volume: 12
• Issue: 7
• Pages: e11099
• DOI: https://doi.org/10.15252/emmm.201911099
• Keywords: ALK/EML4 translocation, NSCLC, ALKi, drug resistance, CDKi
• Publisher URL: https://doi.org/10.15252/emmm.201911099
• Related Public URLs: http://embomolmed.embopress.org/
• Additional Information: Additional Information : ** Article version: VoR ** From Crossref via Jisc Publications Router ** Licence for VoR version of this article starting on 17-06-2020: http://creativecommons.org/licenses/by/4.0/ **Journal IDs: pissn 1757-4676; eissn 1757-4684 **History: issued 17-06-2020; published_online 17-06-2020