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MDM2 as a Rational Target for Intervention in CDK4/6 Inhibitor Resistant, Hormone Receptor Positive Breast Cancer

Neil Portman1,2, Julia Chen1,2, Elgene Lim1,2

  • 1Cancer Theme, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.

Frontiers in Oncology
|November 22, 2021
PubMed

Insights

New treatments are needed for advanced estrogen receptor-positive breast cancer that becomes resistant to cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i). Targeting the p53/MDM2 axis shows promise for overcoming CDK4/6i resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) combined with endocrine therapy are standard for advanced ER+ breast cancer.
  • Therapeutic resistance to CDK4/6i is an inevitable clinical challenge.
  • The p53/MDM2 axis is implicated in CDK4/6i resistance mechanisms.

Purpose of the Study:

  • To review the role of the p53/MDM2 axis in CDK4/6i resistance in ER+ breast cancer.
  • To evaluate preclinical evidence for MDM2 inhibitors in this setting.
  • To discuss targeting the p53/MDM2 axis as a strategy for overcoming CDK4/6i resistance.

Main Methods:

  • Literature review of preclinical studies and mechanistic insights.
  • Analysis of the interplay between CDK4/6, ERα, and p53/MDM2 pathways.
  • Exploration of therapeutic strategies involving MDM2 inhibition.

Main Results:

  • The p53/MDM2 axis is a key mediator in the development of resistance to CDK4/6i.
  • Preclinical data suggest MDM2 inhibitors hold potential efficacy in ER+ breast cancer models.
  • Targeting MDM2 may re-sensitize tumors to CDK4/6i or provide an alternative therapeutic avenue.

Conclusions:

  • The p53/MDM2 axis represents a critical vulnerability in CDK4/6i-resistant ER+ breast cancer.
  • MDM2 inhibitors are a promising therapeutic strategy to investigate in the context of CDK4/6i resistance.
  • Further research into targeting the p53/MDM2 pathway is warranted for advanced breast cancer treatment.
Keywords:
CDK4/6 inhibitorMDM2breast cancerendocrine resistanceestrogen receptor

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