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The Mutant p53-Targeting Compound APR-246 Induces ROS-Modulating Genes in Breast Cancer Cells

Naoise C Synnott1, Stephen F Madden2, Vladimir J N Bykov3

  • 1UCD School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.

Translational Oncology
|September 10, 2018
PubMed

Insights

APR-246 reactivates mutant p53 and affects gene expression in breast cancer cells. Six genes, including SLC7A11 and TRIM16, were upregulated, suggesting potential biomarkers for treatment response.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genomics

Background:

  • The TP53 gene is frequently mutated in human cancers, making mutant p53 a key therapeutic target.
  • APR-246 is an investigational drug designed to reactivate mutant p53 and is in clinical trials for ovarian cancer.
  • Understanding APR-246's molecular effects on gene expression is crucial for optimizing its therapeutic application.

Purpose of the Study:

  • To investigate the effects of APR-246 on gene expression in human breast cancer cell lines using RNA-sequencing.
  • To identify genes and pathways modulated by APR-246 treatment.
  • To explore potential pharmacodynamic biomarkers for APR-246 response.

Main Methods:

  • RNA-sequencing (RNA-seq) was employed to analyze gene expression changes in three human breast cancer cell lines treated with APR-246.
  • Quantitative Polymerase Chain Reaction (qPCR) was used to validate the expression of specific p53 target genes.
  • Gene Ontology (GO) analysis was performed to identify affected biological pathways.

Main Results:

  • APR-246 treatment led to cell line-dependent gene expression changes.
  • Six genes (TRIM16, SLC7A11, TXNRD1, SRXN1, LOC344887, and SLC7A11-AS1) were consistently upregulated across all tested cell lines.
  • While canonical p53 target genes were not significantly upregulated by RNA-seq, qPCR confirmed their induction. GO analysis revealed impacts on oxidative stress, gene expression, cell proliferation, nitrosative stress, and glutathione biosynthesis.

Conclusions:

  • APR-246 exhibits a dual mechanism of action, involving mutant p53 reactivation and redox modulation.
  • Specific genes such as SLC7A11, TRIM16, TXNRD1, and SRXN1 show promise as pharmacodynamic biomarkers for APR-246.
  • These findings support the continued investigation of APR-246 in preclinical and clinical cancer studies.

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