Metabolic compensation activates pro-survival mTORC1 signaling upon 3-phosphoglycerate dehydrogenase inhibition in osteosarcoma

Richa Rathore, Katharine E. Caldwell, Charles Schutt, Caitlyn B. Brashears, Bethany C. Prudner, William R. Ehrhardt, Cheuk Hong Leung, Heather Lin, Najat C. Daw, Hannah C. Beird, Abigail Giles, Wei Lien Wang, Alexander J. Lazar, John S.A. Chrisinger, J. Andrew Livingston, Brian A. Van Tine

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Osteosarcoma is the most common pediatric and adult primary malignant bone cancer. Curative regimens target the folate pathway, downstream of serine metabolism, with high-dose methotrexate. Here, the rate-limiting enzyme in the biosynthesis of serine from glucose, 3-phosphoglycerate dehydrogenase (PHGDH), is examined, and an inverse correlation between PHGDH expression and relapse-free and overall survival in osteosarcoma patients is found. PHGDH inhibition in osteosarcoma cell lines attenuated cellular proliferation without causing cell death, prompting a robust metabolic analysis to characterize pro-survival compensation. Using metabolomic and lipidomic profiling, cellular response to PHGDH inhibition is identified as accumulation of unsaturated lipids, branched chain amino acids, and methionine cycle intermediates, leading to activation of pro-survival mammalian target of rapamycin complex 1 (mTORC1) signaling. Increased mTORC1 activation sensitizes cells to mTORC1 pathway inhibition, resulting in significant, synergistic cell death in vitro and in vivo. Identifying a therapeutic combination for PHGDH-high cancers offers preclinical justification for a dual metabolism-based combination therapy for osteosarcoma.

Original languageEnglish
Article number108678
JournalCell Reports
Volume34
Issue number4
DOIs
StatePublished - Jan 26 2021

Keywords

  • GATOR
  • PHGDH
  • SAMTOR
  • lipid metabolism
  • mTORC1
  • methotrexate
  • one-carbon metabolism
  • osteosarcoma
  • perhexiline
  • serine biosynthesis

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