TY - JOUR

T1 - Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism

AU - Hartleben, Goetz

AU - Schorpp, Kenji

AU - Kwon, Yun

AU - Betz, Barbara

AU - Tsokanos, Foivos Filippos

AU - Dantes, Zahra

AU - Schäfer, Arlett

AU - Rothenaigner, Ina

AU - Monroy Kuhn, José Manuel

AU - Morigny, Pauline

AU - Mehr, Lisa

AU - Lin, Sean

AU - Seitz, Susanne

AU - Tokarz, Janina

AU - Artati, Anna

AU - Adamsky, Jerzy

AU - Plettenburg, Oliver

AU - Lutter, Dominik

AU - Irmler, Martin

AU - Beckers, Johannes

AU - Reichert, Maximilian

AU - Hadian, Kamyar

AU - Zeigerer, Anja

AU - Herzig, Stephan

AU - Berriel Diaz, Mauricio

N1 - Funding Information: This work was supported by an intramural drug development grant to G. H. and M. B. D., M. R., S. H., and M. B. D. are supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, SFB1321 Modeling and Targeting Pancreatic Cancer, Project‐ID 329628492). M. R. is supported by the German Cancer Aid Foundation (Max Eder Program, Deutsche Krebshilfe 111273, M. R.) and the German Research Foundation (RE 3723/4‐1). This work was partially supported by the Helmholtz Alliance “Aging and Metabolic Programming, AMPro” (J. B.; S. H.). We thank Stefan Ambos, Eva Lederer, and Marcos Rios Garcia for technical help and discussions, and Manfred Roesner for advice on drug development. We thank Luke Harrison for his support with figure design. Open Access funding enabled and organized by Projekt DEAL.

PY - 2021/4/9

Y1 - 2021/4/9

N2 - 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.

AB - 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.

KW - cancer metabolism

KW - integrated stress response

KW - metabolic vulnerabilities

KW - pyrimidine metabolism

KW - tricyclic antidepressants

UR - http://www.scopus.com/inward/record.url?scp=85101901759&partnerID=8YFLogxK

U2 - 10.15252/emmm.202012461

DO - 10.15252/emmm.202012461

M3 - Article

C2 - 33665961

AN - SCOPUS:85101901759

VL - 13

JO - EMBO molecular medicine

JF - EMBO molecular medicine

SN - 1757-4676

IS - 4

M1 - e12461

ER -