Inhibition of Cellular MEK/ERK Signaling Suppresses Murine Papillomavirus Type 1 Replicative Activities and Promotes Tumor Regression

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. 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 discovery of the mouse papillomavirus type 1 (MmuPV1) and the development of experimental in vivo infection models in laboratory mice has provided opportunities to study papillomavirus pathogenesis in cutaneous epithelium, the oral cavity, and the anogenital tract. However, the MmuPV1 infection model has not been used to evaluate potential antivirals. We previously reported that inhibitors of cellular MEK/ERK signaling suppress oncogenic HPV early gene expression in vitro. In this report, we adapted the MmuPV1 infection model to determine whether MEK inhibitors have anti-papillomavirus properties in vivo. We demonstrate that oral dosage of the MEK1/2 inhibitor trametinib induces papilloma regression in immunodeficient mice that otherwise would have persistent infections. Moreover, our quantitative histological analyses revealed that inhibition of MEK/ERK signaling reduces E6/E7 mRNAs, MmuPV1 DNA, and L1 protein expression within the 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 from the development of secondary tumors. Thus, our data suggest that MEK inhibitors have potent anti-tumor properties in a preclinical mouse model and merit further investigation as papillomavirus antiviral therapies.

Exploring the Replication Mechanisms of DNA and RNA Viruses

“…Treating pathologically confirmed that the disease aligns with clinical relevance, showing that MEK inhibitors significantly reduce tumor growth by inhibiting cellular proliferation and early PV gene transcription. Targeting both MEK1 and MEK2 is vital for controlling PV disease [66].…”