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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Small Molecule Therapeutics

Repurposing the Antidepressant Sertraline as SHMT Inhibitor to Suppress Serine/Glycine Synthesis–Addicted Breast Tumor Growth

Shauni Lien Geeraerts, Kim Rosalie Kampen, Gianmarco Rinaldi, Purvi Gupta, Mélanie Planque, Nikolaos Louros, Elien Heylen, Kaat De Cremer, Katrijn De Brucker, Stijn Vereecke, Benno Verbelen, Pieter Vermeersch, Joost Schymkowitz, Frederic Rousseau, David Cassiman, Sarah-Maria Fendt, Arnout Voet, Bruno P.A. Cammue, Karin Thevissen and Kim De Keersmaecker
Shauni Lien Geeraerts
1Laboratory for Disease Mechanisms in Cancer, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
2Centre of Microbial and Plant Genetics – Plant Fungi Interactions (CMPG-PFI), KU Leuven, Heverlee, Belgium.
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  • ORCID record for Shauni Lien Geeraerts
Kim Rosalie Kampen
1Laboratory for Disease Mechanisms in Cancer, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
3Maastricht University Medical Center, Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Developmental Biology, Maastricht, the Netherlands.
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Gianmarco Rinaldi
4Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB Leuven, Leuven, Belgium.
5Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
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  • ORCID record for Gianmarco Rinaldi
Purvi Gupta
6Department of Chemistry, KU Leuven, Heverlee, Belgium.
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  • ORCID record for Purvi Gupta
Mélanie Planque
4Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB Leuven, Leuven, Belgium.
5Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
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Nikolaos Louros
7Switch Laboratory, VIB Center for Brain and Disease Research, VIB-KU Leuven, Leuven, Belgium.
8Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
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Elien Heylen
1Laboratory for Disease Mechanisms in Cancer, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
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  • ORCID record for Elien Heylen
Kaat De Cremer
2Centre of Microbial and Plant Genetics – Plant Fungi Interactions (CMPG-PFI), KU Leuven, Heverlee, Belgium.
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Katrijn De Brucker
2Centre of Microbial and Plant Genetics – Plant Fungi Interactions (CMPG-PFI), KU Leuven, Heverlee, Belgium.
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Stijn Vereecke
1Laboratory for Disease Mechanisms in Cancer, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
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Benno Verbelen
1Laboratory for Disease Mechanisms in Cancer, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
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Pieter Vermeersch
9Department of Cardiovascular Sciences, University Hospitals Leuven, Leuven, Belgium.
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Joost Schymkowitz
7Switch Laboratory, VIB Center for Brain and Disease Research, VIB-KU Leuven, Leuven, Belgium.
8Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
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Frederic Rousseau
7Switch Laboratory, VIB Center for Brain and Disease Research, VIB-KU Leuven, Leuven, Belgium.
8Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
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David Cassiman
10Department of Hepatology, University Hospitals Leuven, Leuven, Belgium.
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Sarah-Maria Fendt
4Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB Leuven, Leuven, Belgium.
5Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
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Arnout Voet
6Department of Chemistry, KU Leuven, Heverlee, Belgium.
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Bruno P.A. Cammue
2Centre of Microbial and Plant Genetics – Plant Fungi Interactions (CMPG-PFI), KU Leuven, Heverlee, Belgium.
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Karin Thevissen
2Centre of Microbial and Plant Genetics – Plant Fungi Interactions (CMPG-PFI), KU Leuven, Heverlee, Belgium.
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  • ORCID record for Karin Thevissen
  • For correspondence: kim.dekeersmaecker@kuleuven.be karin.thevissen@kuleuven.be
Kim De Keersmaecker
1Laboratory for Disease Mechanisms in Cancer, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
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  • For correspondence: kim.dekeersmaecker@kuleuven.be karin.thevissen@kuleuven.be
DOI: 10.1158/1535-7163.MCT-20-0480 Published January 2021
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Abstract

Metabolic rewiring is a hallmark of cancer that supports tumor growth, survival, and chemotherapy resistance. Although normal cells often rely on extracellular serine and glycine supply, a significant subset of cancers becomes addicted to intracellular serine/glycine synthesis, offering an attractive drug target. Previously developed inhibitors of serine/glycine synthesis enzymes did not reach clinical trials due to unfavorable pharmacokinetic profiles, implying that further efforts to identify clinically applicable drugs targeting this pathway are required. In this study, we aimed to develop therapies that can rapidly enter the clinical practice by focusing on drug repurposing, as their safety and cost-effectiveness have been optimized before. Using a yeast model system, we repurposed two compounds, sertraline and thimerosal, for their selective toxicity against serine/glycine synthesis–addicted breast cancer and T-cell acute lymphoblastic leukemia cell lines. Isotope tracer metabolomics, computational docking, enzymatic assays, and drug–target interaction studies revealed that sertraline and thimerosal inhibit serine/glycine synthesis enzymes serine hydroxymethyltransferase and phosphoglycerate dehydrogenase, respectively. In addition, we demonstrated that sertraline's antiproliferative activity was further aggravated by mitochondrial inhibitors, such as the antimalarial artemether, by causing G1–S cell-cycle arrest. Most notably, this combination also resulted in serine-selective antitumor activity in breast cancer mouse xenografts. Collectively, this study provides molecular insights into the repurposed mode-of-action of the antidepressant sertraline and allows to delineate a hitherto unidentified group of cancers being particularly sensitive to treatment with sertraline. Furthermore, we highlight the simultaneous inhibition of serine/glycine synthesis and mitochondrial metabolism as a novel treatment strategy for serine/glycine synthesis–addicted cancers.

This article is featured in Highlights of This Issue, p. 1

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2021;20:50–63

  • Received June 11, 2020.
  • Revision received August 19, 2020.
  • Accepted November 3, 2020.
  • Published first November 17, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 20 (1)
January 2021
Volume 20, Issue 1
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Repurposing the Antidepressant Sertraline as SHMT Inhibitor to Suppress Serine/Glycine Synthesis–Addicted Breast Tumor Growth
Shauni Lien Geeraerts, Kim Rosalie Kampen, Gianmarco Rinaldi, Purvi Gupta, Mélanie Planque, Nikolaos Louros, Elien Heylen, Kaat De Cremer, Katrijn De Brucker, Stijn Vereecke, Benno Verbelen, Pieter Vermeersch, Joost Schymkowitz, Frederic Rousseau, David Cassiman, Sarah-Maria Fendt, Arnout Voet, Bruno P.A. Cammue, Karin Thevissen and Kim De Keersmaecker
Mol Cancer Ther January 1 2021 (20) (1) 50-63; DOI: 10.1158/1535-7163.MCT-20-0480

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Repurposing the Antidepressant Sertraline as SHMT Inhibitor to Suppress Serine/Glycine Synthesis–Addicted Breast Tumor Growth
Shauni Lien Geeraerts, Kim Rosalie Kampen, Gianmarco Rinaldi, Purvi Gupta, Mélanie Planque, Nikolaos Louros, Elien Heylen, Kaat De Cremer, Katrijn De Brucker, Stijn Vereecke, Benno Verbelen, Pieter Vermeersch, Joost Schymkowitz, Frederic Rousseau, David Cassiman, Sarah-Maria Fendt, Arnout Voet, Bruno P.A. Cammue, Karin Thevissen and Kim De Keersmaecker
Mol Cancer Ther January 1 2021 (20) (1) 50-63; DOI: 10.1158/1535-7163.MCT-20-0480
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