Human SHMT inhibitors reveal defective glycine import as a targetable metabolic vulnerability of diffuse large B-cell lymphoma

Gregory S. Ducker, Jonathan M. Ghergurovich, Nello Mainolfi, Vipin Suri, Stephanie K. Jeong, Sophia Hsin Jung Li, Adam Friedman, Mark G. Manfredi, Zemer Gitai, Hahn Kim, Joshua D. Rabinowitz

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

The enzyme serine hydroxymethyltransferse (SHMT) converts serine into glycine and a tetrahydrofolate-bound one-carbon unit. Folate one-carbon units support purine and thymidine synthesis, and thus cell growth. Mammals have both cytosolic SHMT1 and mitochondrial SHMT2, with the mitochondrial isozyme strongly up-regulated in cancer. Here we show genetically that dual SHMT1/2 knockout blocks HCT-116 colon cancer tumor xenograft formation. Building from a pyrazolopyran scaffold that inhibits plant SHMT, we identify small-molecule dual inhibitors of human SHMT1/2 (biochemical IC50 ~ 10 nM). Metabolomics and isotope tracer studies demonstrate effective cellular target engagement. A cancer cell-line screen revealed that B-cell lines are particularly sensitive to SHMT inhibition. The one-carbon donor formate generally rescues cells from SHMT inhibition, but paradoxically increases the inhibitor's cytotoxicity in diffuse large B-cell lymphoma (DLBCL). We show that this effect is rooted in defective glycine uptake in DLBCL cell lines, rendering them uniquely dependent upon SHMT enzymatic activity to meet glycine demand. Thus, defective glycine import is a targetable metabolic deficiency of DLBCL.

Original languageEnglish (US)
Pages (from-to)11404-11409
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number43
DOIs
StatePublished - Oct 24 2017

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Cancer metabolism
  • DLBCL
  • Folate
  • Glycine
  • SHMT

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