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MDM2-TP53 Crossregulation: An Underestimated Target to Promote Loss of TP53 Function and Cell Survival

T Soussi1, G Kroemer2

  • 1Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska (CCK) R8:04, Stockholm SE-171 76, Sweden; Université Pierre et Marie Curie, Paris, France; INSERM U1138, Centre de Recherche des Cordeliers, Paris, France; Equipe11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.

Trends in Cancer
|August 29, 2018
PubMed

Insights

Half of human cancers lack TP53 gene mutations but still lose TP53 function due to activated MDM2. This finding suggests MDM2 inhibitors could treat these specific cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • TP53 is a crucial tumor suppressor gene, mutated in about half of all human cancers.
  • The other half of cancers exhibit TP53 inactivation through mechanisms other than direct mutation.
  • Understanding these alternative pathways is vital for developing targeted cancer therapies.

Purpose of the Study:

  • To investigate the role of MDM2 in TP53 inactivation in cancers without TP53 mutations.
  • To explore the therapeutic potential of targeting MDM2 in specific cancer types.

Main Methods:

  • Analysis of TP53 and MDM2 status in liver cancer and medulloblastoma datasets.
  • Investigating the functional consequences of MDM2 activation on TP53 activity.

Main Results:

  • Constitutive activation of MDM2 was observed in liver cancer and medulloblastoma.
  • This MDM2 activation led to the loss of TP53 function, independent of TP53 mutation status.
  • These findings identify a subset of cancers with functional TP53 loss driven by MDM2.

Conclusions:

  • MDM2 activation is a key mechanism for TP53 inactivation in a significant fraction of human cancers.
  • Cancers with constitutively active MDM2 represent a promising target for MDM2 inhibitor therapies.

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