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ResearchIn-Press PreviewDermatologyOncologyVirology Open Access | 10.1172/JCI177724

Integrative analysis reveals therapeutic potential of pyrvinium pamoate in Merkel cell carcinoma

Jiawen Yang,1 James T. Lim,2 Paul Victor Santiago Raj,3 Marcelo G. Corona,1 Chen Chen,1 Hunain Khawaja,1 Qiong Pan,2 Gillian D. Paine-Murrieta,1 Rick G. Schnellmann,3 Denise J. Roe,5 Prafulla C. Gokhale,6 James A. DeCaprio,6 and Megha Padi1

1The University of Arizona Cancer Center, University of Arizona, Tucson, United States of America

2Department of Molecular and Cellular Biology, University of Arizona, Tucson, United States of America

3Department of Pharmacology and Toxicology, University of Arizona, Tucson, United States of America

4Department of Pharmacology and Toxicology, University of Arizona, Tuscon, United States of America

5Department of Epidemiology and Biostatistics, University of Arizona, Tucson, United States of America

6Department of Medical Oncology, Dana Farber Cancer Institute, Boston, United States of America

Find articles by Yang, J. in: JCI | PubMed | Google Scholar

1The University of Arizona Cancer Center, University of Arizona, Tucson, United States of America

2Department of Molecular and Cellular Biology, University of Arizona, Tucson, United States of America

3Department of Pharmacology and Toxicology, University of Arizona, Tucson, United States of America

4Department of Pharmacology and Toxicology, University of Arizona, Tuscon, United States of America

5Department of Epidemiology and Biostatistics, University of Arizona, Tucson, United States of America

6Department of Medical Oncology, Dana Farber Cancer Institute, Boston, United States of America

Find articles by Lim, J. in: JCI | PubMed | Google Scholar

1The University of Arizona Cancer Center, University of Arizona, Tucson, United States of America

2Department of Molecular and Cellular Biology, University of Arizona, Tucson, United States of America

3Department of Pharmacology and Toxicology, University of Arizona, Tucson, United States of America

4Department of Pharmacology and Toxicology, University of Arizona, Tuscon, United States of America

5Department of Epidemiology and Biostatistics, University of Arizona, Tucson, United States of America

6Department of Medical Oncology, Dana Farber Cancer Institute, Boston, United States of America

Find articles by Santiago Raj, P. in: JCI | PubMed | Google Scholar

1The University of Arizona Cancer Center, University of Arizona, Tucson, United States of America

2Department of Molecular and Cellular Biology, University of Arizona, Tucson, United States of America

3Department of Pharmacology and Toxicology, University of Arizona, Tucson, United States of America

4Department of Pharmacology and Toxicology, University of Arizona, Tuscon, United States of America

5Department of Epidemiology and Biostatistics, University of Arizona, Tucson, United States of America

6Department of Medical Oncology, Dana Farber Cancer Institute, Boston, United States of America

Find articles by Corona, M. in: JCI | PubMed | Google Scholar

1The University of Arizona Cancer Center, University of Arizona, Tucson, United States of America

2Department of Molecular and Cellular Biology, University of Arizona, Tucson, United States of America

3Department of Pharmacology and Toxicology, University of Arizona, Tucson, United States of America

4Department of Pharmacology and Toxicology, University of Arizona, Tuscon, United States of America

5Department of Epidemiology and Biostatistics, University of Arizona, Tucson, United States of America

6Department of Medical Oncology, Dana Farber Cancer Institute, Boston, United States of America

Find articles by Chen, C. in: JCI | PubMed | Google Scholar

1The University of Arizona Cancer Center, University of Arizona, Tucson, United States of America

2Department of Molecular and Cellular Biology, University of Arizona, Tucson, United States of America

3Department of Pharmacology and Toxicology, University of Arizona, Tucson, United States of America

4Department of Pharmacology and Toxicology, University of Arizona, Tuscon, United States of America

5Department of Epidemiology and Biostatistics, University of Arizona, Tucson, United States of America

6Department of Medical Oncology, Dana Farber Cancer Institute, Boston, United States of America

Find articles by Khawaja, H. in: JCI | PubMed | Google Scholar

1The University of Arizona Cancer Center, University of Arizona, Tucson, United States of America

2Department of Molecular and Cellular Biology, University of Arizona, Tucson, United States of America

3Department of Pharmacology and Toxicology, University of Arizona, Tucson, United States of America

4Department of Pharmacology and Toxicology, University of Arizona, Tuscon, United States of America

5Department of Epidemiology and Biostatistics, University of Arizona, Tucson, United States of America

6Department of Medical Oncology, Dana Farber Cancer Institute, Boston, United States of America

Find articles by Pan, Q. in: JCI | PubMed | Google Scholar

1The University of Arizona Cancer Center, University of Arizona, Tucson, United States of America

2Department of Molecular and Cellular Biology, University of Arizona, Tucson, United States of America

3Department of Pharmacology and Toxicology, University of Arizona, Tucson, United States of America

4Department of Pharmacology and Toxicology, University of Arizona, Tuscon, United States of America

5Department of Epidemiology and Biostatistics, University of Arizona, Tucson, United States of America

6Department of Medical Oncology, Dana Farber Cancer Institute, Boston, United States of America

Find articles by Paine-Murrieta, G. in: JCI | PubMed | Google Scholar

1The University of Arizona Cancer Center, University of Arizona, Tucson, United States of America

2Department of Molecular and Cellular Biology, University of Arizona, Tucson, United States of America

3Department of Pharmacology and Toxicology, University of Arizona, Tucson, United States of America

4Department of Pharmacology and Toxicology, University of Arizona, Tuscon, United States of America

5Department of Epidemiology and Biostatistics, University of Arizona, Tucson, United States of America

6Department of Medical Oncology, Dana Farber Cancer Institute, Boston, United States of America

Find articles by Schnellmann, R. in: JCI | PubMed | Google Scholar

1The University of Arizona Cancer Center, University of Arizona, Tucson, United States of America

2Department of Molecular and Cellular Biology, University of Arizona, Tucson, United States of America

3Department of Pharmacology and Toxicology, University of Arizona, Tucson, United States of America

4Department of Pharmacology and Toxicology, University of Arizona, Tuscon, United States of America

5Department of Epidemiology and Biostatistics, University of Arizona, Tucson, United States of America

6Department of Medical Oncology, Dana Farber Cancer Institute, Boston, United States of America

Find articles by Roe, D. in: JCI | PubMed | Google Scholar

1The University of Arizona Cancer Center, University of Arizona, Tucson, United States of America

2Department of Molecular and Cellular Biology, University of Arizona, Tucson, United States of America

3Department of Pharmacology and Toxicology, University of Arizona, Tucson, United States of America

4Department of Pharmacology and Toxicology, University of Arizona, Tuscon, United States of America

5Department of Epidemiology and Biostatistics, University of Arizona, Tucson, United States of America

6Department of Medical Oncology, Dana Farber Cancer Institute, Boston, United States of America

Find articles by Gokhale, P. in: JCI | PubMed | Google Scholar

1The University of Arizona Cancer Center, University of Arizona, Tucson, United States of America

2Department of Molecular and Cellular Biology, University of Arizona, Tucson, United States of America

3Department of Pharmacology and Toxicology, University of Arizona, Tucson, United States of America

4Department of Pharmacology and Toxicology, University of Arizona, Tuscon, United States of America

5Department of Epidemiology and Biostatistics, University of Arizona, Tucson, United States of America

6Department of Medical Oncology, Dana Farber Cancer Institute, Boston, United States of America

Find articles by DeCaprio, J. in: JCI | PubMed | Google Scholar |

1The University of Arizona Cancer Center, University of Arizona, Tucson, United States of America

2Department of Molecular and Cellular Biology, University of Arizona, Tucson, United States of America

3Department of Pharmacology and Toxicology, University of Arizona, Tucson, United States of America

4Department of Pharmacology and Toxicology, University of Arizona, Tuscon, United States of America

5Department of Epidemiology and Biostatistics, University of Arizona, Tucson, United States of America

6Department of Medical Oncology, Dana Farber Cancer Institute, Boston, United States of America

Find articles by Padi, M. in: JCI | PubMed | Google Scholar

Published February 11, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI177724.
Copyright © 2025, Yang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 11, 2025 - Version history
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Abstract

Merkel Cell Carcinoma (MCC) is an aggressive neuroendocrine cutaneous malignancy arising from either ultraviolet-induced mutagenesis or Merkel cell polyomavirus (MCPyV) integration. Despite extensive research, our understanding of the molecular mechanisms driving the transition from normal cells to MCC remains limited. To address this knowledge gap, we assessed the impact of inducible MCPyV T antigens on normal human fibroblasts by performing RNA sequencing. Our data uncovered changes in expression and regulation of Wnt signaling pathway members. Building on this observation, we bioinformatically evaluated various Wnt pathway perturbagens for their ability to reverse the MCC gene expression signature and identified pyrvinium pamoate, an FDA-approved anthelminthic drug known for its anti-tumor activity in other cancers. Leveraging transcriptomic, network, and molecular analyses, we found that pyrvinium targets multiple MCC vulnerabilities. Pyrvinium not only reverses the neuroendocrine features of MCC by modulating canonical and non-canonical Wnt signaling but also inhibits cancer cell growth by activating p53-mediated apoptosis, disrupting mitochondrial function, and inducing endoplasmic reticulum stress. Finally, we demonstrated that pyrvinium reduces tumor growth in an MCC mouse xenograft model. These findings offer a new understanding of the role of Wnt signaling in MCC and highlight the utility of pyrvinium as a potential treatment for MCC.

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  • Version 1 (February 11, 2025): In-Press Preview
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