Dual inhibition of MDM2 and MDM4 in virus-positive Merkel cell carcinoma enhances the p53 response

Academic Article


  • Significance Merkel cell carcinoma (MCC) is an aggressive skin cancer. While virus-negative [Merkel cell polyomavirus (MCV)] MCC contains inactivating mutations in RB and p53, MCV-positive MCC usually contains wild-type RB and p53. We demonstrate that MCV large T antigen binding to RB results in p53 activation, while MCV small T antigen reduces p53 activation by increasing levels of MDM2 and CK1 α , an activator of MDM4. Targeted degradation of CK1 α by lenalidomide or a specific MDM4 inhibitor acts synergistically with MDM2 inhibitors to activate p53 and induce apoptosis. Our work uncovers the mechanism behind MCV control of p53 in MCC and demonstrates the utility of targeting MDM2 and MDM4 combinatorially in p53 wild-type tumors.
  • Authors

  • Park, Donglim Esther
  • Cheng, Jingwei
  • Berrios, Christian
  • Montero, Joan
  • Cortés-Cros, Marta
  • Ferretti, Stéphane
  • Arora, Reety
  • Tillgren, Michelle L
  • Gokhale, Prafulla C
  • DeCaprio, James A
  • Status

    Publication Date

  • January 15, 2019
  • Keywords

  • Carcinoma, Merkel Cell/genetics/*metabolism/pathology/virology DNA Helicases/genetics/metabolism DNA-Binding Proteins/genetics/metabolism Humans Merkel cell polyomavirus/genetics/*metabolism Nuclear Proteins/antagonists & inhibitors/genetics/*metabolism Polyomavirus Infections/genetics/*metabolism/pathology Proto-Oncogene Proteins/antagonists & inhibitors/genetics/*metabolism Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors/genetics/*metabolism Retinoblastoma Binding Proteins/genetics/metabolism Tumor Suppressor Protein p53/genetics/*metabolism Tumor Virus Infections/genetics/*metabolism/pathology Ubiquitin-Protein Ligases/genetics/metabolism *mdm2-mdm4 *Merkel cell carcinoma *casein kinase 1 alpha *lenalidomide *p53 Institute for Biomedical Research. R.A. was supported by Wellcome Trust DBT India Alliance Early Career Fellowship IA/E/14/1/501773. A patent was filed with the related work.
  • Digital Object Identifier (doi)

    Start Page

  • 1027
  • End Page

  • 1032
  • Volume

  • 116
  • Issue

  • 3