The Antiviral Effects of a MEK1/2 Inhibitor Promote Tumor Regression in a Preclinical Model of Human Papillomavirus Infection-Induced Tumorigenesis

Authors

Adrian J. Luna, Department of Molecular Genetics & Microbiology, The University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA.
Jesse M. Young, Department of Molecular Genetics & Microbiology, The University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA.
Rosa T. Sterk, Department of Molecular Genetics & Microbiology, The University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA.
Virginie Bondu, Department of Molecular Genetics & Microbiology, The University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA.
Fred A. Schultz, Department of Pathology, The University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA.
Donna F. Kusewitt, Department of Pathology, The University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA; The University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, 87131, USA.
Huining Kang, Department of Internal Medicine, Division of Epidemiology, Biostatistics and Preventive Medicine, The University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA; The University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, 87131, USA.
Michelle A. Ozbun, Department of Molecular Genetics & Microbiology, The University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA; The University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, 87131, USA.Follow

Document Type

Article

Publication Date

8-1-2023

Abstract

Human papillomaviruses (HPVs) are a significant public health concern due to their widespread transmission, morbidity, and oncogenic potential. Despite efficacious vaccines, millions of unvaccinated individuals and those with existing infections will develop HPV-related diseases for the next two decades and beyond. The continuing burden of HPV-related diseases is exacerbated by the lack of effective therapies or cures for infections, highlighting the need to identify and develop antivirals. The experimental murine papillomavirus type 1 (MmuPV1) model provides opportunities to study papillomavirus pathogenesis in cutaneous epithelium, the oral cavity, and the anogenital tract. However, to date the MmuPV1 infection model has not been used to demonstrate the effectiveness of potential antivirals. We previously reported that inhibitors of cellular MEK/ERK signaling suppress oncogenic HPV early gene expression in three-dimensional tissue cultures. Herein, we adapted the MmuPV1 infection model to determine whether MEK inhibitors have anti-papillomavirus properties in vivo. We demonstrate that oral delivery of a MEK1/2 inhibitor promotes papilloma regression in immunodeficient mice that otherwise would have developed persistent infections. Quantitative histological analyses reveal that inhibition of MEK/ERK signaling reduces E6/E7 mRNA, MmuPV1 DNA, and L1 protein expression within MmuPV1-induced lesions. These data suggest that MEK1/2 signaling is essential for both early and late MmuPV1 replication events supporting our previous findings with oncogenic HPVs. We also provide evidence that MEK inhibitors protect mice from developing secondary tumors. Thus, our data suggest that MEK inhibitors have potent antiviral and anti-tumor properties in a preclinical mouse model and merit further investigation as papillomavirus antiviral therapies.

Recommended Citation

Luna AJ, Young JM, Sterk RT, Bondu V, Schultz FA, Kusewitt DF, Kang H, Ozbun MA. The antiviral effects of a MEK1/2 inhibitor promote tumor regression in a preclinical model of human papillomavirus infection-induced tumorigenesis. Antiviral Res. 2023 Aug;216:105667. doi: 10.1016/j.antiviral.2023.105667. Epub 2023 Jul 8. PMID: 37429527; PMCID: PMC10530289.