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Metabolic Reprogramming by MYCN Confers Dependence on the Serine-Glycine-One-Carbon Biosynthetic Pathway

Yingfeng Xia1, Bingwei Ye2, Jane Ding2

  • 1Institute of Neural Regeneration and Repair and Department of Neurology, The First Hospital of Yichang, Three Gorges University College of Medicine, Yichang, China.

Cancer Research
|May 16, 2019
PubMed

Insights

MYCN amplification in cancers creates a metabolic vulnerability by increasing reliance on the serine-glycine-one-carbon (SGOC) pathway. Inhibiting this pathway selectively kills cancer cells, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Metabolic Pathways
  • Cancer Biology

Background:

  • MYCN amplification is a key driver of pediatric and adult neuronal cancers.
  • Directly targeting MYCN presents therapeutic challenges.
  • Identifying MYCN-activated metabolic pathways is crucial for novel drug development.

Purpose of the Study:

  • To investigate MYCN-activated metabolic pathways as potential therapeutic targets.
  • To understand the role of the serine-glycine-one-carbon (SGOC) pathway in MYCN-amplified cancers.
  • To explore the therapeutic potential of targeting the SGOC pathway.

Main Methods:

  • Analysis of transcriptional activation of the SGOC pathway in neuroblastoma cells.
  • Assessment of cellular dependence on the SGOC pathway for biosynthesis.
  • Evaluation of small molecule inhibitors targeting the SGOC pathway in cell lines and xenografts.
  • Investigation of the MYCN-ATF4 feedback loop involving FBXW7.

Main Results:

  • MYCN-amplified neuroblastoma cells exhibit increased SGOC pathway activation and dependence.
  • Small molecule inhibitors of the SGOC pathway demonstrate selective cytotoxicity against MYCN-amplified cancers.
  • Inhibition of the SGOC pathway induces metabolic stress and autophagy.
  • A positive feedback loop between MYCN and ATF4 regulates SGOC pathway activation.

Conclusions:

  • The SGOC pathway is a MYCN-dependent metabolic vulnerability in neuronal cancers.
  • Targeting the SGOC pathway offers a selective therapeutic strategy for MYCN-amplified cancers.
  • A coupled relationship exists between metabolic reprogramming and sensitivity to metabolic stress in these cancers.

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