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

Abstract

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.

• Authors: Goetz Hartleben, Kenji Schorpp, Yun Kwon, Barbara Betz, Foivos-Filippos Tsokanos, Zahra Dantes, Arlett Schäfer, Ina Rothenaigner, José Manuel Monroy Kuhn, Pauline Morigny, Lisa Mehr, Sean Lin, Susanne Seitz, Janina Tokarz, Anna Artati, Jerzy Adamsky, Oliver Plettenburg, Dominik Lutter, Martin Irmler, Johannes Beckers, Maximilian Reichert, Kamyar Hadian, Anja Zeigerer, Stephan Herzig, Mauricio Berriel Diaz
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 13 Issue 4 Pg. e12461 (04 09 2021) ISSN: 1757-4684 [Electronic] England
• PMID: 33665961 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Published under the terms of the CC BY 4.0 license.

Chemical References

• Antineoplastic Agents
• Pyrimidines
• Niclosamide

Topics

• Antineoplastic Agents
• Cell Death
• Humans
• Neoplasms
• Niclosamide
• Pyrimidines