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Hartleben, G. ; Schorpp, K.K. ; Kwon, Y. ; Betz, B. ; Tsokanos, F.-F. ; Dantes, Z.* ; Schäfer, A.* ; Rothenaigner, I. ; Monroy Kuhn, J.M. ; Morigny, P. ; Mehr, L. ; Lin, S. ; Seitz, S. ; Tokarz, J. ; Artati, A. ; Adamski, J. ; Plettenburg, O. ; Lutter, D. ; Irmler, M. ; Beckers, J. ; Reichert, M.* ; Hadian, K. ; Zeigerer, A. ; Herzig, S. ; Berriel Diaz, M.

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

EMBO Mol. Med.:e12461 (2021)

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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

Corresponding Author

Keywords Cancer Metabolism ; Integrated Stress Response ; Metabolic Vulnerabilities ; Pyrimidine Metabolism ; Tricyclic Antidepressants

ISSN (print) / ISBN 1757-4676

e-ISSN 1757-4684

Journal EMBO Molecular Medicine

Quellenangaben Article Number: e12461

Publisher Wiley

Publishing Place Chichester

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Diabetes and Cancer (IDC)
Institute of Molecular Toxicology and Pharmacology (TOXI)
Institute of Diabetes and Obesity (IDO)
Molekulare Endokrinologie und Metabolismus (MEM)
Institute of Medicinal Chemistry (IMC)
Institute of Experimental Genetics (IEG)
CF Metabolomics & Proteomics (CF-MPC)

Grants Helmholtz Alliance "Aging and Metabolic Programming, AMPro"
German Research Foundation