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Single Droplet Digital Polymerase Chain Reaction for Comprehensive and Simultaneous Detection of Mutations in Hotspot Regions
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Published on: September 25, 2018

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Hotspot SF3B1 mutations induce metabolic reprogramming and vulnerability to serine deprivation

W Brian Dalton1, Eric Helmenstine1, Noel Walsh1

  • 1Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, and.

The Journal of Clinical Investigation
|August 9, 2019
PubMed

Insights

Cancer-associated SF3B1 mutations alter cell metabolism and create vulnerabilities. Restricting serine and glycine in mice inhibited tumor growth, suggesting a new therapeutic strategy for SF3B1-mutant cancers.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Metabolic Pathways

Background:

  • Cancer-associated mutations in SF3B1 lead to aberrant mRNA splicing.
  • The biological and therapeutic consequences of this missplicing are not well understood.

Purpose of the Study:

  • To investigate the downstream effects of SF3B1 mutations on cellular processes.
  • To identify potential therapeutic vulnerabilities associated with SF3B1 mutations.

Main Methods:

  • Analysis of transcriptome, proteome, and metabolome in human cells with mutant SF3B1.
  • In vitro and in vivo studies assessing the impact of serine and glycine deprivation on cancer cell growth and tumor xenografts.

Main Results:

  • Mutant SF3B1 altered cellular metabolism, decreasing mitochondrial respiration and suppressing the serine synthesis pathway.
  • SF3B1 mutations induced a vulnerability to serine deprivation, mediated by downregulation of PHGDH.
  • Dietary restriction of serine and glycine inhibited the growth of SF3B1-mutant xenografts in mice.

Conclusions:

  • SF3B1 mutations play a role in altered energy metabolism in cancer.
  • Targeting serine metabolism presents a potential therapeutic strategy for SF3B1-mutant cancers.
Keywords:
Amino acid metabolismCancerMetabolismOncology

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