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Updated: Jun 20, 2025

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Targeting YES1 Disrupts Mitotic Fidelity and Potentiates the Response to Taxanes in Triple-Negative Breast Cancer

Katrina M Piemonte1,2, Natasha N Ingles2,3, Kristen L Weber-Bonk2

  • 1Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio.

Cancer Research
|July 22, 2024
PubMed

Insights

Targeting YES1, a key kinase in triple-negative breast cancer (TNBC), enhances chemotherapy efficacy. Disrupting YES1 improves outcomes by stabilizing genome integrity and boosting taxane effectiveness in TNBC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Broad-spectrum Src family kinase (SFK) inhibitors cause dose-limiting toxicities in solid tumors.
  • Targeting individual SFKs offers a strategy to improve efficacy and reduce toxicity.
  • YES1 is the most overexpressed SFK in triple-negative breast cancer (TNBC), correlating with poor patient outcomes.

Purpose of the Study:

  • To investigate the role of YES1 in TNBC pathogenesis and its potential as a therapeutic target.
  • To explore the mechanism by which YES1 influences genomic stability and mitotic progression.
  • To evaluate the therapeutic potential of YES1 inhibition in combination with standard TNBC treatments.

Main Methods:

  • Genetic and pharmacological disruption of YES1 in TNBC cell lines and animal models.
  • Analysis of mitotic aberrations, centrosome amplification, and chromosomal instability.
  • Investigation of the molecular pathway involving YES1, FOXM1, and centrosome function.
  • Assessment of YES1 expression in clinical TNBC samples and correlation with patient survival.

Main Results:

  • YES1 disruption induced aberrant mitosis, centrosome amplification, and chromosomal instability.
  • YES1 was found to sustain FOXM1 protein levels, crucial for centrosome function and mitotic progression.
  • YES1 suppression potentiated the efficacy of taxanes in both in vitro and in vivo TNBC models.
  • Elevated YES1 expression correlated with worse survival in TNBC patients treated with taxane-anthracycline regimens.

Conclusions:

  • YES1 is a critical regulator of genome stability in TNBC.
  • Targeting YES1 represents a promising therapeutic strategy to enhance taxane efficacy in TNBC.
  • The YES1-FOXM1 pathway is a significant therapeutic vulnerability in triple-negative breast cancer.

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