2. Academic Validation
  3. SHMT inhibition is effective and synergizes with methotrexate in T-cell acute lymphoblastic leukemia

SHMT inhibition is effective and synergizes with methotrexate in T-cell acute lymphoblastic leukemia

  • Leukemia. 2021 Feb;35(2):377-388. doi: 10.1038/s41375-020-0845-6.
Juan C García-Cañaveras # 1 2 3,  Olga Lancho # 4,  Gregory S Ducker 1 2 5,  Jonathan M Ghergurovich 1 6,  Xincheng Xu 1 2,  Victoria da Silva-Diz 4,  Sonia Minuzzo 7,  Stefano Indraccolo 8,  Hahn Kim 2 9,  Daniel Herranz 10 11,  Joshua D Rabinowitz 12 13
Affiliations

Affiliations

  • 1 Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, 08544, USA.
  • 2 Department of Chemistry, Princeton University, Princeton, NJ, 08544, USA.
  • 3 Biomarkers and Precision Medicine Unit and Analytical Unit, Instituto de Investigación Sanitaria Fundación Hospital La Fe, 46026, València, Spain.
  • 4 Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, 08901, USA.
  • 5 Department of Biochemistry, University of Utah, Salt Lake City, UT, 84112, USA.
  • 6 Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA.
  • 7 Department of Surgery, Oncology and Gastroenterology, University of Padova, 35124, Padua, Italy.
  • 8 Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128, Padua, Italy.
  • 9 Princeton University Small Molecule Screening Center, Princeton University, Princeton, NJ, 08544, USA.
  • 10 Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, 08901, USA. [email protected].
  • 11 Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, 08854, USA. [email protected].
  • 12 Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, 08544, USA. [email protected].
  • 13 Department of Chemistry, Princeton University, Princeton, NJ, 08544, USA. [email protected].
  • # Contributed equally.
PMID: 32382081 DOI: 10.1038/s41375-020-0845-6
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.

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