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BH3-mimetics or DNA-damaging agents in combination with RG7388 overcome p53 mutation-induced resistance to MDM2

N V Pervushin1,2, D K Nilov3, S V Pushkarev4

  • 1Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia.

Apoptosis : an International Journal on Programmed Cell Death
|September 2, 2024
PubMed

Insights

Drug resistance in cancer therapy can arise from mutations in the p53 protein, impacting MDM2 inhibitor efficacy. Combination therapies with Cisplatin and BH3-mimetics show promise in overcoming this resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Drug resistance diminishes the effectiveness of cancer treatments.
  • MDM2 inhibitors are a promising class of cancer drugs currently in clinical trials.
  • Acquired resistance to MDM2 inhibitors poses a significant challenge in neuroblastoma and other cancers.

Purpose of the Study:

  • To investigate the mechanisms of resistance to MDM2 inhibitors in neuroblastoma.
  • To characterize the phenotypic and molecular changes associated with RG7388 resistance.
  • To identify potential strategies for overcoming MDM2 inhibitor resistance.

Main Methods:

  • Generation of RG7388-resistant neuroblastoma cell lines.
  • Assessment of cellular proliferation and metabolic activity.
  • Evaluation of sensitivity to DNA-damaging agents and MDM2 inhibition.
  • Analysis of p53 protein mutation and its effect on transcriptional activity.
  • Testing combination therapies including Cisplatin and BH3-mimetics.

Main Results:

  • RG7388-resistant cells exhibited increased proliferation and metabolic activity.
  • Resistance was linked to a p53 His193Arg mutation, impairing its transcriptional function by destabilizing the p53-DNA complex.
  • This p53 mutation was found in various cancer types.
  • Cisplatin and BH3-mimetics partially restored RG7388-induced apoptosis in resistant cells.

Conclusions:

  • p53 mutations are a key mechanism of resistance to MDM2 inhibitors.
  • The His193Arg p53 mutation compromises MDM2 inhibitor efficacy by affecting p53 transcriptional activity.
  • Combination therapy with Cisplatin and BH3-mimetics offers a potential strategy to overcome MDM2 inhibitor resistance in neuroblastoma.
Keywords:
BH3-mimeticsDrug resistanceMDM2RG7388p53 mutation

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