Content area
Abstract
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 13C-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.
Details
; Lancho Olga 2 ; Ducker, Gregory S 3 ; Ghergurovich, Jonathan M 4
; Xu Xincheng 5 ; da Silva-Diz Victoria 2 ; Minuzzo Sonia 6 ; Indraccolo Stefano 7 ; Hahn, Kim 8 ; Herranz, Daniel 9
; Rabinowitz, Joshua D 5
1 Princeton University, Lewis Sigler Institute for Integrative Genomics, Princeton, USA (GRID:grid.16750.35) (ISNI:0000 0001 2097 5006); Princeton University, Department of Chemistry, Princeton, USA (GRID:grid.16750.35) (ISNI:0000 0001 2097 5006); Instituto de Investigación Sanitaria Fundación Hospital La Fe, Biomarkers and Precision Medicine Unit and Analytical Unit, València, Spain (GRID:grid.476458.c)
2 Rutgers University, Rutgers Cancer Institute of New Jersey, New Brunswick, USA (GRID:grid.430387.b) (ISNI:0000 0004 1936 8796)
3 Princeton University, Lewis Sigler Institute for Integrative Genomics, Princeton, USA (GRID:grid.16750.35) (ISNI:0000 0001 2097 5006); Princeton University, Department of Chemistry, Princeton, USA (GRID:grid.16750.35) (ISNI:0000 0001 2097 5006); University of Utah, Department of Biochemistry, Salt Lake City, USA (GRID:grid.223827.e) (ISNI:0000 0001 2193 0096)
4 Princeton University, Lewis Sigler Institute for Integrative Genomics, Princeton, USA (GRID:grid.16750.35) (ISNI:0000 0001 2097 5006); Princeton University, Department of Molecular Biology, Princeton, USA (GRID:grid.16750.35) (ISNI:0000 0001 2097 5006)
5 Princeton University, Lewis Sigler Institute for Integrative Genomics, Princeton, USA (GRID:grid.16750.35) (ISNI:0000 0001 2097 5006); Princeton University, Department of Chemistry, Princeton, USA (GRID:grid.16750.35) (ISNI:0000 0001 2097 5006)
6 University of Padova, Department of Surgery, Oncology and Gastroenterology, Padua, Italy (GRID:grid.5608.b) (ISNI:0000 0004 1757 3470)
7 Veneto Institute of Oncology IOV-IRCCS, Immunology and Molecular Oncology Unit, Padua, Italy (GRID:grid.419546.b) (ISNI:0000 0004 1808 1697)
8 Princeton University, Department of Chemistry, Princeton, USA (GRID:grid.16750.35) (ISNI:0000 0001 2097 5006); Princeton University, Princeton University Small Molecule Screening Center, Princeton, USA (GRID:grid.16750.35) (ISNI:0000 0001 2097 5006)
9 Rutgers University, Rutgers Cancer Institute of New Jersey, New Brunswick, USA (GRID:grid.430387.b) (ISNI:0000 0004 1936 8796); Rutgers University, Department of Pharmacology, Robert Wood Johnson Medical School, Piscataway, USA (GRID:grid.430387.b) (ISNI:0000 0004 1936 8796)