Opposing Interplay between Nuclear Factor Erythroid 2-Related Factor 2 and Forkhead BoxO 1/3 is Responsible for

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Updated: Jun 26, 2025

Utilizing Functional Genomics Screening to Identify Potentially Novel Drug Targets in Cancer Cell Spheroid Cultures
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Utilizing Functional Genomics Screening to Identify Potentially Novel Drug Targets in Cancer Cell Spheroid Cultures

Published on: December 26, 2016

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Shaista Haider1, Shayantani Chakraborty1, Goutam Chowdhury2

  • 1Department of Life Sciences, Shiv Nadar Institution of Eminence, Greater Noida Gautam Buddha Nagar Uttar Pradesh 201314, India.

ACS Pharmacology & Translational Science
|May 16, 2024
PubMed

Insights

Survivin-targeting drug YM155 resistance in triple-negative breast cancer involves a feedback loop between NRF2 and FoxO transcription factors. Interrupting this interaction restores drug sensitivity and enhances cancer cell clearance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Survivin is a key cancer protein and therapeutic target, but survivin-targeting agents lack clinical approval due to complex regulatory feedback loops.
  • The phosphatidylinositol 3-kinase/AKT serine-threonine kinase/forkhead boxO (PI3K/AKT/FoxO) pathway is implicated in survivin regulation through molecular cross-talk.
  • Triple-negative breast cancer (TNBC) cells exhibit high survivin expression, making them a relevant model for studying survivin-targeting therapies.

Purpose of the Study:

  • To investigate the mechanisms of resistance to survivin-suppressant sepantronium bromide (YM155) in triple-negative breast cancer (TNBC) cells.
  • To identify novel signaling pathway cross-talk contributing to YM155 resistance.
  • To explore therapeutic strategies for overcoming YM155 resistance and enhancing anti-cancer effects.

Main Methods:

  • Utilized sepantronium bromide (YM155) to study survivin regulation and drug resistance in TNBC cells.
  • Investigated the cross-talk between Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) and FoxO transcription factors.
  • Employed pharmacological manipulation to disrupt identified signaling interactions.
  • Assessed the impact of interventions on drug sensitivity and cancer cell immune clearance.

Main Results:

  • Discovered a novel feedback loop between NRF2 and FoxO transcription factors that contributes to YM155 resistance in TNBC cells.
  • YM155-induced reactive oxygen species (ROS) initiate this feedback mechanism.
  • Pharmacological interruption of the NRF2-FoxO interaction restored and enhanced YM155 sensitivity.
  • The combined approach led to effective immune clearance of cancer cells.

Conclusions:

  • The identified NRF2-FoxO cross-talk explains the limited clinical efficacy of YM155 observed in trials.
  • This feedback loop is likely relevant for other ROS-producing chemotherapeutic agents.
  • A triple drug combination strategy may reintroduce YM155 into clinical use, particularly for TNBC treatment due to high survivin expression.

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