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Targeted MDM2 Degradation Reveals a New Vulnerability for p53-Inactivated Triple-Negative Breast Cancer

Clare M Adams1, Ramkrishna Mitra1, Youcai Xiao2

  • 1Department of Pharmacology, Physiology, and Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.

Cancer Discovery
|February 3, 2023
PubMed

Insights

A novel PROteolysis TArgeting Chimera (PROTAC) drug effectively targets MDM2, a protein crucial for triple-negative breast cancer (TNBC) survival. This breakthrough therapy induces cancer cell death while sparing healthy cells, offering a promising new treatment for aggressive TNBC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Triple-negative breast cancer (TNBC) often inactivates the p53 tumor suppressor, leading to increased aggressiveness and resistance to therapies.
  • p53-inactivated TNBC represents a significant unmet medical need due to its aggressive nature and poor prognosis.

Purpose of the Study:

  • To identify and exploit a novel protein vulnerability in p53-inactivated TNBC.
  • To design and evaluate a targeted therapeutic agent for p53-inactivated TNBC.

Main Methods:

  • Development of a PROteolysis TArgeting Chimera (PROTAC) designed to selectively degrade MDM2.
  • Assessment of PROTAC efficacy in 2D/3D cell cultures, patient explants, and TNBC xenograft mouse models.
  • Transcriptomic analysis and investigation of downstream signaling pathways, including p53 family members.

Main Results:

  • The developed MDM2-PROTAC selectively induced proteasomal degradation of MDM2 in p53-inactivated TNBC cells.
  • MDM2 degradation resulted in apoptosis of TNBC cells, including those from relapsed tumors, while sparing normal cells.
  • In vivo studies demonstrated on-target efficacy, significant tumor reduction, extended survival, and no observed toxicity in mice.
  • Activation of TAp73 was identified as essential for mediating PROTAC-induced apoptosis.

Conclusions:

  • MDM2 is essential for the survival of p53-inactivated TNBC cells, contrary to the traditional p53/MDM2 paradigm.
  • PROTAC-mediated MDM2 degradation represents a novel and potentially superior therapeutic strategy for TNBC compared to existing MDM2 inhibitors.
  • This approach offers a promising new avenue for treating aggressive and therapy-resistant TNBC.

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