TY - JOUR
T1 - Repurposing the antidepressant sertraline as SHMT inhibitor to suppress serine/glycine synthesis–addicted breast tumor growth
AU - Geeraerts, Shauni Lien
AU - Kampen, Kim Rosalie
AU - Rinaldi, Gianmarco
AU - Gupta, Purvi
AU - Planque, Melanie
AU - Louros, Nikolaos
AU - Heylen, Elien
AU - de Cremer, Kaat
AU - de Brucker, Katrijn
AU - Vereecke, Stijn
AU - Verbelen, Benno
AU - Vermeersch, Pieter
AU - Schymkowitz, Joost
AU - Rousseau, Frederic
AU - Cassiman, David
AU - Fendt, Sarah Maria
AU - Voet, Arnout
AU - Cammue, Bruno P.A.
AU - Thevissen, Karin
AU - de Keersmaecker, Kim
N1 - Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1535-7163.MCT-20-0480
DO - 10.1158/1535-7163.MCT-20-0480
M3 - Article
C2 - 33203732
AN - SCOPUS:85099978099
SN - 1535-7163
VL - 20
SP - 50
EP - 63
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 1
ER -