Transcriptional effects of inhibiting epidermal growth factor receptor in keratinocytes

AbstractBackgroundEpidermal growth factor receptor (EGFR) activation is important in human epithelial malignancies, including cutaneous squamous cell carcinoma, lung, colon, pancreatic, and other cancers. Therapies targeting EGFR are currently used to treat such cancers, but one significant drawback to EGFR inhibitor therapies is the associated skin toxicity. This toxicity usually presents as papular or pustular folliculitis, dry skin with pruritus and hair and nail abnormalities. The side effects often limit the usefulness of EGFR inhibitors in cancer treatment. The transcriptional changes caused by EGFR inhibition in epidermal keratinocytes have not been extensively explored.MethodsTo define the transcriptional changes caused by inhibition of EGFR in primary human epidermal keratinocytes, these cells were treated with Tyrphostin AG1478 and treated and control cultures were compared in parallel, using Affymetrix microarrays. Using meta-analysis approaches, the observed changes were integrated with a large set of already existing data on transcriptional profiling in epidermal keratinocytes.ResultsWe found that at the early time points, 1 hour and 4 hours after addition, AG1478 suppresses expression of genes associated with keratinocyte proliferation, attachment and motility. Apoptosis is facilitated by both induction of proapoptotic and suppression of antiapoptotic genes. Angiogenesis signals are suppressed as well. At late time points, 24 hours and 48 hours, EGFR inhibition induces mitochondrial activity and suppresses splicing and protein trafficking. Certain transcriptional effects of EGFR inhibition go against the transcriptional effects of retinoids. Surprisingly, at 48 hours, EGFR inhibition induces expression of markers of epidermal differentiation.ConclusionOur results define the role of EGF receptor in human keratinocytes and the consequences of its inhibition