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<p>Osteosarcoma is a bone cancer that has been found to be metabolically dependent on the conversion of glucose to serine through the rate-limiting enzyme 3-phosphoglycerate dehydrogenase (PHGDH). The upregulation of PHGDH has been correlated with poor patient survival, and the inhibition of the serine synthesis pathway using targeted small-molecule inhibition of PHGDH induces a rapid metabolic adaptation that prevents cell death due to pro-survival signaling through the mammalian target of rapamycin complex 1 (mTORC1) pathway. Here, PHGDH inhibition in combination with mTORC1 signaling modulation for the treatment of osteosarcoma was evaluated. When combined with PHGDH inhibition, several non-rapalog inhibitors of mTORC1 activated Forkhead box O (FOXO) transcription factor 3 (FOXO3), a transcription factor associated with various cellular processes driving apoptosis. The activation of FOXO3 led to transcriptional activation of the pro-apoptotic gene p53 upregulated modulator of apoptosis (PUMA), inducing apoptosis when combined with PHGDH inhibition. These data suggest a path for the clinical development of PHGDH inhibitors in conjunction with mTORC1 pathway modulators in osteosarcoma.</p>

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PHGDH inhibition and FOXO3 modulation drives PUMA-dependent apoptosis in osteosarcoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月12日

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  • Toshinao Oyama,
  • Caitlyn B. Brashears,
  • Richa Rathore,
  • Heather Benect-Hamilton,
  • Katharine E. Caldwell,
  • Naomi Dirckx,
  • William G. Hawkins,
  • Brian A. Van Tine

摘要

Osteosarcoma is a bone cancer that has been found to be metabolically dependent on the conversion of glucose to serine through the rate-limiting enzyme 3-phosphoglycerate dehydrogenase (PHGDH). The upregulation of PHGDH has been correlated with poor patient survival, and the inhibition of the serine synthesis pathway using targeted small-molecule inhibition of PHGDH induces a rapid metabolic adaptation that prevents cell death due to pro-survival signaling through the mammalian target of rapamycin complex 1 (mTORC1) pathway. Here, PHGDH inhibition in combination with mTORC1 signaling modulation for the treatment of osteosarcoma was evaluated. When combined with PHGDH inhibition, several non-rapalog inhibitors of mTORC1 activated Forkhead box O (FOXO) transcription factor 3 (FOXO3), a transcription factor associated with various cellular processes driving apoptosis. The activation of FOXO3 led to transcriptional activation of the pro-apoptotic gene p53 upregulated modulator of apoptosis (PUMA), inducing apoptosis when combined with PHGDH inhibition. These data suggest a path for the clinical development of PHGDH inhibitors in conjunction with mTORC1 pathway modulators in osteosarcoma.