The second mechanism involves direct effects on STAT1. Cells treated with EGF and IFN have lower levels of STAT1 homodimerization than cells treated with IFN alone, suggesting that EGFR signaling impairs STAT1 function. Erlotinib rescued the repressive effect of EGF on IFN-induced STAT1 homodimerization, which correlated with Epigenetics inhibitor a concomitant rescue in ISG expression levels. Thus, in this mechanism, erlotinib relieves the repressive effect of EGFR on STAT1 function, thereby promoting antiviral gene expression and shifting the pathway in a direction that favors the host. This two-pronged mechanism of erlotinib action suggests that EGFR inhibition may be a useful way to boost the antiviral
Autophagy activator efficacy of IFN. The intersection of IFN and EGFR pathways described
in this study provides novel insight into cellular signaling cross-talk. These studies also provide a starting point to go deeper into the mechanisms of EGFR antagonism of IFN pathways. For example, EGFR impairs IFN-mediated STAT3, but not STAT1, phosphorylation. However, STAT1 homodimerization is affected. Thus, EGFR signaling may affect JAK1/tyrosine kinase 2 kinase activities and/or impair release of phosphorylated STAT1 from the cytoplasmic tail of the IFN-α receptor. Interestingly, the negative regulation of IFN signaling by EGFR described here will need to be examined in the context of a recent study showing cross-talk between Toll-like receptor 3 (TLR3) and EGFR.[11] In fibroblasts, EGFR was shown to be required for TLR3 signaling and downstream
antiviral responses. Thus, EGFR may play positive and negative regulatory roles with respect to antiviral immune signaling. Additional studies will be needed to delineate the context and specificity much of these newly described roles for EGFR. This study also points to potential implications of EGFR inhibition in the clinic. The researchers suggest that erlotinib may have value in the treatment of patients chronically infected with HCV, particularly in “hard-to-treat” patient populations. If so, the putative benefits would, of course, have to be weighed in comparison to the potential adverse effects of augmented IFN responses, as well as known side effects of erlotinib in cancer patients.[12] Moreover, given the rapidly changing landscape of therapies for HCV, it is unclear how much longer IFN will be a mainstay of HCV treatment. Indeed, a major goal in the field is to eliminate the use of IFN in lieu of more targeted drug cocktails that have fewer side effects. IFN-free regimens are already showing remarkable potential in early clinical trials, with sustained virological response rates equal to or above those observed with IFN-based therapies.[13] As the drugs and treatments improve, particularly in hard-to-treat patient populations, IFN’s future as an HCV therapy remains uncertain.