TitleDual inhibition of MDM2 and MDM4 in virus-positive Merkel cell carcinoma enhances the p53 response.
Publication TypeJournal Article
Year of Publication2019
AuthorsPark DEsther, Cheng J, Berrios C, Montero J, Cortés-Cros M, Ferretti S, Arora R, Tillgren ML, Gokhale PC, DeCaprio JA
JournalProc Natl Acad Sci U S A
Volume116
Issue3
Pagination1027-1032
Date Published2019 Jan 15
ISSN1091-6490
Abstract

Merkel cell polyomavirus (MCV) contributes to approximately 80% of all Merkel cell carcinomas (MCCs), a highly aggressive neuroendocrine carcinoma of the skin. MCV-positive MCC expresses small T antigen (ST) and a truncated form of large T antigen (LT) and usually contains wild-type p53 (TP53) and RB (RB1). In contrast, virus-negative MCC contains inactivating mutations in TP53 and RB1. While the MCV-truncated LT can bind and inhibit RB, it does not bind p53. We report here that MCV LT binds to RB, leading to increased levels of ARF, an inhibitor of MDM2, and activation of p53. However, coexpression of ST reduced p53 activation. MCV ST recruits the MYC homologue MYCL (L-Myc) to the EP400 chromatin remodeler complex and transactivates specific target genes. We observed that depletion of EP400 in MCV-positive MCC cell lines led to increased p53 target gene expression. We suspected that the MCV ST-MYCL-EP400 complex could functionally inactivate p53, but the underlying mechanism was not known. Integrated ChIP and RNA-sequencing analysis following EP400 depletion identified MDM2 as well as CK1α, an activator of MDM4, as target genes of the ST-MYCL-EP400 complex. In addition, MCV-positive MCC cells expressed high levels of MDM4. Combining MDM2 inhibitors with lenalidomide targeting CK1α or an MDM4 inhibitor caused synergistic activation of p53, leading to an apoptotic response in MCV-positive MCC cells and MCC-derived xenografts in mice. These results support dual targeting of MDM2 and MDM4 in virus-positive MCC and other p53 wild-type tumors.

DOI10.1073/pnas.1818798116
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID30598450
PubMed Central IDPMC6338866
Grant List / / Wellcome Trust / United Kingdom