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

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

doi:10.1073/pnas.1818798116

Cited by 72 publications

(102 citation statements)

References 36 publications

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“…A region of Chr1q (cluster 13) was amplified in 28 cases. This region includes MDM4 (also known as MDMX), whose protein product cooperates with MDM2 to promote the ubiquitination and subsequent degradation of p53 ( Figure 2B) (27,28). In addition, we observed March 23, 2019 a focal amplification of MYCL in Chr1p (cluster 4), which was reported in an earlier study of MCC (29).…”

Section: Somatic Variant Analysis Of Targeted Sequencingsupporting

confidence: 82%

Clinical and molecular characterization of virus-positive and virus-negative Merkel cell carcinoma

Starrett¹,

Chen

Marcelus

et al. 2019

Preprint

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Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine carcinoma of the skin mediated by the integration of Merkel cell polyomavirus (MCPyV) and expression of viral T antigens or by ultraviolet induced damage to the tumor genome from excessive sunlight exposure. An increasing number of deep sequencing studies of MCC have identified significant differences between the number and types of point mutations, copy number alterations, and structural variants between virus-positive and virus-negative tumors. In this study, we assembled a cohort of 71 MCC patients and performed deep sequencing with OncoPanel, a next-generation sequencing assay targeting over 400 cancer-associated genes. To improve the accuracy and sensitivity for virus detection compared to traditional PCR and IHC methods, we developed a hybrid capture baitset against the entire MCPyV genome. The viral baitset identified integration junctions in the tumor genome and generated assemblies that strongly support a model of a hybrid, virus-host, circular DNA intermediate during integration that promotes focal amplification of host DNA. Using the clear delineation between virus-positive and virus-negative tumors from this method, we identified recurrent somatic alterations common across MCC and alterations specific to each class of tumor, associated with differences in overall survival. Comparing the molecular and clinical data from these patients revealed a surprising association of immunosuppression with virus-negative MCC and significantly shortened overall survival. These results demonstrate the value of high-confidence virus detection for identifying clinically important features in MCC that impact patient outcome. March 23, 2019 not initiating event in virus-positive MCC oncogenesis. MCPyV infects most people, typically at an early age, and results in an asymptomatic and lifelong infection indicated by the presence of antibodies to the viral coat protein VP1 (3, 4). Although MCPyV DNA can be readily detected on the skin, the cell types where the virus replicates in vivo have not been determined (5).Since the original discovery of MCPyV, it has become increasingly clear that virus-positive MCC has a different etiology than virus-negative MCC (1). While virus-positive MCC expresses the viral oncogenes Large T antigen (LT) and Small T antigen (ST), the tumor genome usually contains very few mutations in cellular oncogenes and tumor suppressor genes. In contrast, studies using whole exome or targeted hybrid capture sequencing have revealed that virusnegative MCC has an exceptionally high somatic mutation load predominated by UV-mediated mutations with frequent mutations in RB1, TP53, NOTCH1, and FAT1 (6,7). Whole genome sequencing (WGS) of MCC confirmed virus-positive MCC exhibits a globally lower, non-UVmediated, mutation burden as well as few somatic copy number amplifications, deletions, and rearrangements compared to virus-negative MCC, while providing new insights into the structure and mechanism of virus integration (8).Accurate detection of ...

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Section: Somatic Variant Analysis Of Targeted Sequencingsupporting

confidence: 82%

Clinical and molecular characterization of virus-positive and virus-negative Merkel cell carcinoma

Starrett¹,

Chen

Marcelus

et al. 2019

Preprint

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“…The inhibition of MDM2 could be also effective in a neuroendocrine carcinoma of the skin called Merkel cell carcinomas, which is caused by Merkel cell polyomavirus. The double inhibition of MDM2 and MDM4 could activate p53, leading to apoptosis of virus-infected cells [52].…”

Section: High Degree Centrality Gene Study and Potential Drug Therapymentioning

confidence: 99%

In Silico Discovery of Candidate Drugs against Covid-19

Cava

Bertoli

Castiglioni

2020

Viruses

178

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Previous studies reported that Angiotensin converting enzyme 2 (ACE2) is the main cell receptor of SARS-CoV and SARS-CoV-2. It plays a key role in the access of the virus into the cell to produce the final infection. In the present study we investigated in silico the basic mechanism of ACE2 in the lung and provided evidences for new potentially effective drugs for Covid-19. Specifically, we used the gene expression profiles from public datasets including The Cancer Genome Atlas, Gene Expression Omnibus and Genotype-Tissue Expression, Gene Ontology and pathway enrichment analysis to investigate the main functions of ACE2-correlated genes. We constructed a protein-protein interaction network containing the genes co-expressed with ACE2. Finally, we focused on the genes in the network that are already associated with known drugs and evaluated their role for a potential treatment of Covid-19. Our results demonstrate that the genes correlated with ACE2 are mainly enriched in the sterol biosynthetic process, Aryldialkylphosphatase activity, adenosylhomocysteinase activity, trialkylsulfonium hydrolase activity, acetate-CoA and CoA ligase activity. We identified a network of 193 genes, 222 interactions and 36 potential drugs that could have a crucial role. Among possible interesting drugs for Covid-19 treatment, we found Nimesulide, Fluticasone Propionate, Thiabendazole, Photofrin, Didanosine and Flutamide.While the diagnosis of COVID-19 is based on the amplification of the viral genome in real-time PCR with specific probes, the current treatment of affected individuals is limited to a mixture of a broad-spectrum of antiviral drugs [6]. However, in many cases this pharmacological approach has proven to be totally ineffective.Screening drug studies on pangolin SARS-CoV-2, which is the human-related Coronavirus, demonstrated that three drugs (cepharanthine, selamectin and mefloquine hydrochloride) were effective in inhibiting viral replication, with cepharanthine potently inhibiting coronavirus infection at viral entry and post-entry viral replication [7]. The last drug is an anti-inflammatory and antineoplastic alkaloid approved for leukopenia and it is also proposed to inhibit the human immunodeficiency virus type 1 (HIV) entering in cells by reducing plasma membrane fluidity. In humans, it has a reduced toxicity.Mefloquine is the approved treatment for malaria and has antiviral activity against both MERS-CoV and SARS-CoV [8]. The antiviral mechanism of selamectin is still unknown, as it is used usually as a topical broad-spectrum parasiticide in little animals (e.g., cats and dogs).The entry of the virus in the cells is mediated by spike (S) glycoprotein; in particular, the spike 1 (S1) surface unit allows the attachment of the virus to cellular receptors. To allow the entry of the viral particles, the S protein is cleaved by cellular proteases at the S1/S2 and the S2 site. Then, the viral capside is fused with the cellular membrane, a process driven by the S2 subunit [9]. It has been described that SARS-CoV entrance is ...

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“…KRT‐232 is currently under investigation for patients with wild‐type TP53 who have failed anti‐PD‐1 or anti‐PD‐L1 therapy (NCT03787602). Furthermore, MCPyV‐sT reduces p53 activation by increasing levels of MDM2 and casein kinase‐1α (CK1α), an activator of MDM4 . Targeted degradation of CK1α by lenalidomide or specific MDM4 inhibitors, coupled with inhibition of MDM2, may act synergistically against wild‐type p53 …”

Section: Discussionmentioning

confidence: 99%

Molecular and immune targets for Merkel cell carcinoma therapy and prevention

Cohen

Tsai

2019

Molecular Carcinogenesis

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Merkel cell carcinoma (MCC) is a rare neuroendocrine carcinoma of the skin, for which the exact mechanisms of carcinogenesis remain unknown. Therapeutic options for this highly aggressive malignancy have historically been limited in both their initial response and response durability. Recent improvements in our understanding of MCC tumor biology have expanded therapeutic options for these patients, namely through the use of immunotherapies such as immune checkpoint inhibitors. Further elucidation of the tumor mutational landscape has identified molecular targets for therapies, which have demonstrated success in other cancer types. In this review, we discuss both current and investigational immune and molecular targets of therapy for MCC.

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

Cited by 72 publications

References 36 publications

Clinical and molecular characterization of virus-positive and virus-negative Merkel cell carcinoma

Clinical and molecular characterization of virus-positive and virus-negative Merkel cell carcinoma

In Silico Discovery of Candidate Drugs against Covid-19

Molecular and immune targets for Merkel cell carcinoma therapy and prevention

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