Related Experiment Video

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Detection of Aggregation-Prone Behavior in Mutant P53 V157F Breast Cancer Cells Using Multipoint Thioflavin T Fluorescence
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Detection of Aggregation-Prone Behavior in Mutant P53 V157F Breast Cancer Cells Using Multipoint Thioflavin T Fluorescence

Published on: December 30, 2025

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Mutant p53-Nrf2 axis regulates the proteasome machinery in cancer

Kamil Lisek1, Dawid Walerych1, Giannino Del Sal2

  • 1Laboratorio Nazionale CIB, Area Science Park Padriciano , Trieste, Italy.

Molecular & Cellular Oncology
|February 16, 2017
PubMed

Insights

Targeting mutant p53 proteins with APR-246 overcomes chemoresistance in triple-negative breast cancer. This approach counters the Nrf2-regulated "bounce-back" response that upregulates proteasome machinery, enhancing drug efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The proteasome is a cellular machine targeted by p53 mutations.
  • Proteasome upregulation leads to chemoresistance against proteasome inhibitors.
  • Triple-negative breast cancer (TNBC) exhibits a specific resistance mechanism involving Nrf2.

Purpose of the Study:

  • To investigate if targeting mutant p53 proteins can overcome chemoresistance in TNBC.
  • To evaluate the efficacy of APR-246/PRIMA-1Met in overcoming the Nrf2-regulated resistance.
  • To understand the interplay between p53 mutations, proteasome activity, and chemoresistance in TNBC.

Main Methods:

  • Utilized triple-negative breast cancer cell lines.
  • Administered APR-246/PRIMA-1Met, a p53-targeting therapeutic.
  • Assessed proteasome activity and Nrf2 pathway regulation.
  • Measured chemoresistance levels to proteasome inhibitors.

Main Results:

  • Gain-of-function p53 missense mutants commonly target proteasome machinery.
  • Upregulation of the proteasome confers chemoresistance to proteasome inhibitors.
  • APR-246/PRIMA-1Met effectively targets p53 mutant proteins.
  • The Nrf2-regulated "bounce-back" resistance mechanism in TNBC was overcome by APR-246/PRIMA-1Met.

Conclusions:

  • Targeting mutant p53 proteins with APR-246 is a viable strategy to overcome chemoresistance in TNBC.
  • APR-246 disrupts the Nrf2-mediated proteasome upregulation, resensitizing cancer cells to proteasome inhibitors.
  • This highlights a novel therapeutic approach for chemoresistant TNBC.
Keywords:
APR-246Chip-seqKeap1Nrf2TNBCcancermulti-omicsmutant p53proteasomeproteomicstranscriptomics

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