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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Inhibiting the system xC-/glutathione axis selectively targets cancers with mutant-p53 accumulation

David S Liu1,2,3, Cuong P Duong2, Sue Haupt1

  • 1Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.

Nature Communications
|March 29, 2017
PubMed

Insights

Targeting mutant-TP53 cancers is crucial. Mutant-p53 suppresses SLC7A11, creating vulnerabilities exploitable by system xC- inhibitors and APR-246, offering new therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • TP53 gene mutations are prevalent in over 50% of human cancers, leading to mutant-p53 accumulation and reduced patient survival.
  • Targeting cancers with mutant-p53 represents a significant unmet clinical need.

Purpose of the Study:

  • To investigate the mechanism by which mutant-p53 affects cancer cell vulnerabilities.
  • To identify novel therapeutic strategies targeting mutant-p53 cancers.
  • To evaluate SLC7A11 as a predictive biomarker for APR-246 therapy.

Main Methods:

  • Investigated the interaction between mutant-p53, NRF2, and SLC7A11 expression.
  • Utilized system xC- inhibitors to target cancer cells.
  • Assessed SLC7A11 expression as a biomarker for APR-246 efficacy.
  • Examined the synergistic effects of system xC- antagonism and APR-246.

Main Results:

  • Accumulated mutant-p53 protein suppresses SLC7A11 expression by binding to NRF2, reducing glutathione synthesis and increasing oxidative stress susceptibility in mutant-p53 tumors.
  • System xC- inhibitors selectively kill cancer cells with stabilized mutant-p53.
  • SLC7A11 expression serves as a predictive biomarker for APR-246, a mutant-p53 reactivator.
  • Combined system xC- antagonism and APR-246 synergistically induce apoptosis in mutant-p53 tumors.

Conclusions:

  • Inhibiting the SLC7A11-glutathione axis presents a promising therapeutic strategy for cancers with accumulated mutant-p53.
  • SLC7A11 expression is a valuable predictive biomarker for APR-246 therapy.
  • Combination therapy with system xC- inhibitors and APR-246 offers a synergistic approach to treat mutant-p53 cancers.

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