Apoptotic Responses Triggered in Dual-Targeted Virus-Positive Merkel Cell Carcinomas
Posted: Thursday, January 24, 2019
Research published in the Proceedings of the National Academy of Sciences found that targeting both MDM2 and MDM4 in Merkel cell polyomavirus (MCV)-positive Merkel cell carcinoma augments the apoptosis-inducing p53 response. “Our work uncovers the mechanism behind MCV control of p53 in Merkel cell carcinoma and demonstrates the utility of targeting MDM2 and MDM4 combinatorially in p53 wild-type tumors,” noted James A. DeCaprio, MD, of Harvard University, Dana-Farber Cancer Center, Boston, and colleagues.
Virus-positive Merkel cell carcinoma, known to express small T antigen and a shortened version of large T antigen, typically contains wild-type p53 and retinoblastoma susceptibility gene. The MCV large T antigen can bind to the retinoblastoma susceptibility gene, releasing an increased amount of alternative reading frame proteins (ARF), which stymie MDM2. This leads to the activation of p53, which is in turn hindered by the co-expression of the small T antigen, which enlists MYCL to the EP400 chromatin remodeler complex and transactivates certain genes. However, researchers found that a reduction in EP400 led to an increase in p53 expression in virus-positive Merkel cell carcinoma cells.
The investigators uncovered the mechanism for this response through ChIP and RNA-sequencing analysis, which revealed both MDM2 and MDM4-activator CK1α to be target genes of the small T antigen-MYCL-EP400 complex after EP400 reduction. When an MDM2 inhibitor was introduced with either lenalidomide, which targets CK1α, or an MDM4 inhibitor, the combination spurred a synergistic p53 activation. This led to apoptosis in both virus-positive Merkel cell carcinoma cells as well as Merkel cell carcinoma–derived xenografts in mice.
Disclosure: The study authors’ disclosure information may be found at pnas.org.