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

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

  • EMBO Mol Med. 2021 Apr 9;13(4):e12461. doi: 10.15252/emmm.202012461.
Goetz Hartleben 1 2 3,  Kenji Schorpp 4,  Yun Kwon 1 2 3,  Barbara Betz 1 2 3,  Foivos-Filippos Tsokanos 1 2 3,  Zahra Dantes 5,  Arlett Schäfer 5,  Ina Rothenaigner 4,  José Manuel Monroy Kuhn 6,  Pauline Morigny 1 2 3,  Lisa Mehr 1 2 3,  Sean Lin 4,  Susanne Seitz 1 2 3,  Janina Tokarz 7,  Anna Artati 7,  Jerzy Adamsky 3 7 8 9,  Oliver Plettenburg 10 11,  Dominik Lutter 6,  Martin Irmler 12,  Johannes Beckers 3 12 13,  Maximilian Reichert 5 14 15,  Kamyar Hadian 4,  Anja Zeigerer 1 2 3,  Stephan Herzig 1 2 3 16,  Mauricio Berriel Diaz 1 2 3
Affiliations

Affiliations

  • 1 Institute for Diabetes and Cancer, Helmholtz Center Munich, Neuherberg, Germany.
  • 2 Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg University Hospital, Heidelberg, Germany.
  • 3 German Center for Diabetes Research (DZD), Neuherberg, Germany.
  • 4 Assay Development and Screening Platform, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München, Neuherberg, Germany.
  • 5 Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
  • 6 Institute for Diabetes and Obesity, Neuherberg, Germany.
  • 7 Research Unit Molecular Endocrinology and Metabolism, Helmholtz Center Munich, Neuherberg, Germany.
  • 8 Lehrstuhl für Experimentelle Genetik, Technische Universtität München, Freising-Weihenstephan, Germany.
  • 9 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore City, Singapore.
  • 10 Institute of Medicinal Chemistry, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
  • 11 Institute of Organic Chemistry, Center of Biomolecular Drug Research (BMWZ), Leibniz University Hannover, Hannover, Germany.
  • 12 Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, Neuherberg, Germany.
  • 13 Technische Universität München, Chair of Experimental Genetics, Freising, Germany.
  • 14 Center for Protein Assemblies (CPA), Technische Universität München, Garching, Germany.
  • 15 German Cancer Consortium (DKTK), Munich, Germany.
  • 16 Chair Molecular Metabolic Control, Technical University Munich, Munich, Germany.
PMID: 33665961 DOI: 10.15252/emmm.202012461
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.

Keywords

cancer metabolism; integrated stress response; metabolic vulnerabilities; pyrimidine metabolism; tricyclic antidepressants.

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