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

Paliouras, AR, Buzzetti, M ORCID: https://orcid.org/0000-0003-3415-0982, Shi, L, Donaldson, IJ, Magee, P, Sahoo, S, Leong, H‐S, Fassan, M, Carter, M, Di Leva, G, Krebs, MG, Blackhall, F, Lovly, CM and Garofalo, M ORCID: https://orcid.org/0000-0002-1741-0415 2020, 'Vulnerability of drug‐resistant EML4‐ALK rearranged lung cancer to transcriptional inhibition' , EMBO Molecular Medicine, 12 (7) , e11099.

[img]
Preview
PDF - Published Version
Available under License Creative Commons Attribution 4.0.

Download (3MB) | Preview

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.

Item Type: Article
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
Uncontrolled Keywords: Molecular Medicine
Schools: Schools > School of Environment and Life Sciences > Biomedical Research Centre
Journal or Publication Title: EMBO Molecular Medicine
Publisher: EMBO
ISSN: 1757-4684
Related URLs:
Funders: Cancer Research UK (CRUK)
SWORD Depositor: Publications Router
Depositing User: Publications Router
Date Deposited: 29 Jun 2020 08:43
Last Modified: 16 Jul 2020 15:00
URI: http://usir.salford.ac.uk/id/eprint/57464

Actions (login required)

Edit record (repository staff only) Edit record (repository staff only)

Downloads

Downloads per month over past year