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Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism.

EMBO Mol. Med.:e12461 (2021)
Publ. Version/Full Text DOI
Open Access Gold
Creative Commons Lizenzvertrag
By accentuating drug efficacy and impeding resistance mechanisms, combinatorial, multi-agent therapies have emerged as key approaches in the treatment of complex diseases, most notably cancer. Using high-throughput drug screens, we uncovered distinct metabolic vulnerabilities and thereby identified drug combinations synergistically causing a starvation-like lethal catabolic response in tumor cells from different cancer entities. Domperidone, a dopamine receptor antagonist, as well as several tricyclic antidepressants (TCAs), including imipramine, induced cancer cell death in combination with the mitochondrial uncoupler niclosamide ethanolamine (NEN) through activation of the integrated stress response pathway and the catabolic CLEAR network. Using transcriptome and metabolome analyses, we characterized a combinatorial response, mainly driven by the transcription factors CHOP and TFE3, which resulted in cell death through enhanced pyrimidine catabolism as well as reduced pyrimidine synthesis. Remarkably, the drug combinations sensitized human organoid cultures to the standard-of-care chemotherapy paclitaxel. Thus, our combinatorial approach could be clinically implemented into established treatment regimen, which would be further facilitated by the advantages of drug repurposing.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Cancer Metabolism ; Integrated Stress Response ; Metabolic Vulnerabilities ; Pyrimidine Metabolism ; Tricyclic Antidepressants
ISSN (print) / ISBN 1757-4676
e-ISSN 1757-4684
Quellenangaben Volume: , Issue: , Pages: , Article Number: e12461 Supplement: ,
Publisher Wiley
Publishing Place Chichester
Reviewing status Peer reviewed
Grants Helmholtz Alliance "Aging and Metabolic Programming, AMPro"
German Research Foundation