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Vulnerability of drug-resistant EML4-ALK rearranged lung cancer to transcriptional inhibition
Paliouras, Athanasios R Buzzetti, M Shi, Lei Donaldson, IJ Magee, Peter Sahoo, Sudhakar Leong, Hui Sun Fassan, M Carter, Mathew Di Leva, G
Paliouras, Athanasios R
Buzzetti, M
Shi, Lei
Donaldson, IJ
Magee, Peter
Sahoo, Sudhakar
Leong, Hui Sun
Fassan, M
Carter, Mathew
Di Leva, G
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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.
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Date
2020
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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.