Vulnerability of Drug-resistant EML4-ALK Rearranged Lung Cancer to Transcriptional Inhibition

Overview

Journal EMBO Mol Med

Specialty Molecular Biology

Date 2020 Jun 20

PMID 32558295

Citations 9

Authors

Athanasios R Paliouras

Marta Buzzetti

Lei Shi

Ian J Donaldson

Peter Magee

Sudhakar Sahoo

Hui-Sun Leong

Matteo Fassan

Matthew Carter

Gianpiero Di Leva

Matthew G Krebs

Fiona Blackhall

Christine M Lovly

Michela Garofalo

Affiliations

Soon will be listed here.

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.

Citing Articles

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DNA methylome and single-cell transcriptome analyses reveal CDA as a potential druggable target for ALK inhibitor-resistant lung cancer therapy.

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