Park, Donglim Esther, Cheng, Jingwei, Berrios, Christian, Montero, Joan, Cortes-Cros, Marta, Ferretti, Stephane Raymond, Arora, Reety, Tillgren, Michelle, Gokhale, Prafulla and DeCaprio, James A. (2019) Dual Inhibition of MDM2 and MDM4 in Virus-Positive Merkel Cell Carcinoma Enhances the p53 Response. Proceedings of the National Academy of Sciences of the United States of America PNAS., 116 (3). pp. 1027-1032. ISSN 0027-8424

Abstract

Merkel cell polyomavirus (MCV) contributes to approximately 80%
of all Merkel cell carcinomas (MCC), 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,
co-expression 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-seq analysis following EP400 depletion identified
MDM2 as well as CK1�, 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 CK1� 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.

Item Type:	Article
Date Deposited:	06 Feb 2019 00:45
Last Modified:	06 Feb 2019 00:45
URI:	https://oak.novartis.com/id/eprint/37562