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

Fecha de publicación: 07/05/2020 Fecha Ahead of Print: 07/05/2020

Autores de IIS La Fe

Juan Carlos García Cañaveras

Autor

Participantes ajenos a IIS La Fe

Lancho O
Ducker GS
Ghergurovich JM
Xu X
da Silva-Diz V
Minuzzo S
Indraccolo S
Kim H
Herranz D
Rabinowitz JD

Grupos

Unidad de Biomarcadores y Medicina de Precisión (UBYMP)

Leader

Agustín Lahoz Rodríguez

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 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.

Datos de la publicación

ISSN/ISSNe:: 0887-6924, 1476-5551
Tipo:: Article
Páginas:: 377-388
DOI:: 10.1038/s41375-020-0845-6
Factor de Impacto:: 4,539 SCImago ℠
Cuartil:: Q1 SCImago ℠

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Métricas

Filiaciones

García-Cañaveras JC:: Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, 08544, USA

Department of Chemistry, Princeton University, Princeton, NJ, 08544, USA

Instituto de Investigación. Biomarkers and Precision Medicine Unit and Analytical Unit, Instituto de Investigación Sanitaria Fundación Hospital La Fe, 46026, València, Spain
Lancho O:: Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, 08901, USA
Ducker GS:: Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, 08544, USA

Department of Chemistry, Princeton University, Princeton, NJ, 08544, USA

Department of Biochemistry, University of Utah, Salt Lake City, UT, 84112, USA
Ghergurovich JM:: Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, 08544, USA

Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA
Xu X:: Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, 08544, USA

Department of Chemistry, Princeton University, Princeton, NJ, 08544, USA
da Silva-Diz V:: Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, 08901, USA
Minuzzo S:: Department of Surgery, Oncology and Gastroenterology, University of Padova, 35124, Padua, Italy
Indraccolo S:: Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128, Padua, Italy
Kim H:: Department of Chemistry, Princeton University, Princeton, NJ, 08544, USA

Princeton University Small Molecule Screening Center, Princeton University, Princeton, NJ, 08544, USA
Herranz D:: Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, 08901, USA.

Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, 08854, USA.
Rabinowitz JD:: Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, 08544, USA.

Department of Chemistry, Princeton University, Princeton, NJ, 08544, USA.