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SHMT inhibition is effective and synergizes with methotrexate in T-cell acute lymphoblastic leukemia
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SHMT inhibition is effective and synergizes with methotrexate in T-cell acute lymphoblastic leukemia
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Journal Article
SHMT inhibition is effective and synergizes with methotrexate in T-cell acute lymphoblastic leukemia
2021
Overview
Folate metabolism enables cell growth by providing one-carbon (1C) units for nucleotide biosynthesis. The 1C units are carried by tetrahydrofolate, whose production by the enzyme dihydrofolate reductase is targeted by the important anticancer drug methotrexate. 1C units come largely from serine catabolism by the enzyme serine hydroxymethyltransferase (SHMT), whose mitochondrial isoform is strongly upregulated in cancer. Here we report the SHMT inhibitor SHIN2 and demonstrate its in vivo target engagement with
13
C-serine tracing. As methotrexate is standard treatment for T-cell acute lymphoblastic leukemia (T-ALL), we explored the utility of SHIN2 in this disease. SHIN2 increases survival in NOTCH1-driven mouse primary T-ALL in vivo. Low dose methotrexate sensitizes Molt4 human T-ALL cells to SHIN2, and cells rendered methotrexate resistant in vitro show enhanced sensitivity to SHIN2. Finally, SHIN2 and methotrexate synergize in mouse primary T-ALL and in a human patient-derived xenograft in vivo, increasing survival. Thus, SHMT inhibition offers a complementary strategy in the treatment of T-ALL.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 64/60
/ 82/16
/ 82/58
/ Acute lymphoblastic leukemia
/ Animals
/ Antimetabolites, Antineoplastic - pharmacology
/ Enzymes
/ Gene Expression Regulation, Leukemic
/ Glycine Hydroxymethyltransferase - antagonists & inhibitors
/ Humans
/ Leukemia
/ Male
/ Medicine
/ Mice
/ Oncology
/ Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism
/ Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology
/ Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - therapy
/ Serine
/ Survival
