Imatinib mesylate, commercially known as Gleevec/Glivec, is the first targeted anticancer drug that inhibits activity of the tyrosine kinases, c-ABL, c-KIT, and PDGFR. A number of studies have shown that treatment with imatinib mesylate elicits extracellular signal-related kinase (ERK) activation, which, in turn, has been shown to confer radioresistance. Here, we investigated whether treatment with imatinib mesylate protects skin-derived epithelial cells, including normal keratinocytes, immortalized HaCaT and A431 cancer cell lines, from the effects of gamma-radiation. ERK activation was detected 30 min after imatinib mesylate treatment in all three cell lines. In cells exposed to gamma-irradiation in the presence of imatinib mesylate, this activation of ERK was associated with a reduction in radiation-induced apoptosis and enhanced cell survival. Similar effects of imatinib mesylate treatment were observed following gamma-irradiation of a three-dimensional human skin culture system that reproduces a fully differentiated epithelium. Collectively, our findings provide the evidence of a protective effect of imatinib mesylate against the effects of gamma-irradiation on epithelial-derived cells, regardless of their malignancy status. (C) 2018 Elsevier Inc. All rights reserved.