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EZH2 PROTACs target EZH2- and FOXM1-associated oncogenic nodes, suppressing breast cancer cell growth

Joshua Corbin1,2, Xufen Yu3,4, Jian Jin3,4

  • 1Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA.

Oncogene
|August 7, 2024
PubMed

Insights

Proteolysis targeting chimeras (PROTACs) targeting Enhancer of zeste homolog 2 (EZH2) effectively treat tamoxifen-resistant breast cancer by degrading EZH2 and FOXM1. This approach shows promise for overcoming treatment resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Breast cancer (BC) is a leading cause of cancer mortality in women.
  • Tamoxifen resistance is a significant clinical challenge in BC treatment.
  • Enhancer of zeste homolog 2 (EZH2) is implicated in tamoxifen resistance, functioning both canonically and noncanonically.

Purpose of the Study:

  • To investigate the efficacy of EZH2-targeted proteolysis targeting chimeras (PROTACs) against tamoxifen-resistant breast cancer.
  • To elucidate the molecular mechanisms underlying the action of EZH2 PROTACs.

Main Methods:

  • Utilized EZH2 PROTACs (MS177 and MS8815) in breast cancer cell models, including tamoxifen-resistant lines.
  • Compared the efficacy of PROTACs with traditional methyltransferase inhibitors.
  • Investigated the interaction between EZH2 and forkhead box M1 (FOXM1) and their target gene regulation.

Main Results:

  • EZH2 PROTACs significantly inhibited the growth of both sensitive and tamoxifen-resistant breast cancer cells.
  • PROTACs demonstrated superior efficacy compared to methyltransferase inhibitors.
  • EZH2 PROTACs induced degradation of both EZH2 and FOXM1, reducing the expression of key genes involved in cell cycle and tamoxifen resistance.

Conclusions:

  • EZH2 PROTACs are effective against tamoxifen-resistant breast cancer.
  • Targeting EZH2 degradation via PROTACs offers a promising therapeutic strategy for overcoming treatment resistance in breast cancer.
  • The dual degradation of EZH2 and FOXM1 is a key mechanism of action.

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