Inhibition of EGFR Signal Transduction in Human Keratinocytes Infected with Oncogenic HPV Leads to a Decrease in Viral Transcript Levels and Genome Numbers

Human Papillomaviruses (HPVs) are known to cause 99.9% of cervical cancers as well as subsets of anogenital and oropharygeal cancers.  Vaccination against the two most common oncogenic HPV types (HPV-16 and -18) has proven effective in decreasing the number of infected individuals.  However, the prohibitively high cost of the vaccines and low uptake rate continue to limit their effectiveness.  Therefore, continuing research on prophylactic and therapeutic interventions is needed.  It has previously been shown that HPV early proteins regulate EGFR expression and recycling in infected cells.  Although many epithelial cancers have increased EGFR expression, there are conflicting data regarding EGFR expression levels in tissues collected from HPV infected lesions.  Our lab has proposed that HPV infection establishes an intracellular positive feedback loop with the EGFR signaling pathway that does not require high levels of EGFR expression.  This feedback loop results in increased EGFR pathway signal transduction leading to enhanced viral transcription through modulation of cell survival and proliferation functions.  In the present study, the effect of EGFR and MAPK inhibitors on viral transcription, genome maintenance, and cell viability was tested on cells containing oncogenic HPV genomes.  Our results indicate that EGFR pathway inhibitors lead to a reduction in viral early transcripts and genome copies in these cell types in vitro.  These results suggest that EGFR pathway inhibitor(s) may be useful in the treatment of HPV infected lesions in lieu of or concurrent with removal of infected, abnormal tissue.