Off-target serine/threonine kinase 10 inhibition by erlotinib enhances lymphocytic activity leading to severe skin disorders.

Skin disorders are among the most common adverse events related to treatment with epidermal growth factor receptor (EGFR) kinase inhibitors, and of these, erlotinib is known to cause more frequent and severe skin disease than other agents in this class. Although previous reports have shown that cutaneous manifestations are triggered by the inhibition of multiple EGFR-related homeostatic functions of the skin, this mechanism alone cannot explain the differences in frequency and severity of skin disorders caused by different kinase inhibitors. In this study, we focused on the relationship between the off-target kinase inhibition and aggravation of skin disorders. Based on calculations using reported K(d) values and plasma drug concentrations, serine/threonine kinase 10 (STK10) and Ste20-like kinase (SLK) were selected as candidates preferentially inhibited by erlotinib over gefitinib. In vitro experiments confirmed that STK10 and SLK kinase activity are inhibited by erlotinib at clinical concentrations, whereas only STK10 is slightly inhibited by gefitinib. It was also shown that erlotinib up-regulated lymphocytic responses such as interleukin (IL)-2 secretion and cell migration at clinical concentrations, whereas gefitinib did not affect lymphocyte activity. Moreover, small interfering RNA experiments revealed that STK10 plays a major role in up-regulation of the lymphocytic responses induced by erlotinib treatment. Finally, the role of erlotinib-induced lymphocyte activation was assessed in vivo using irritant hypersensitivity models. The results indicated that erlotinib aggravates cutaneous inflammatory reactions through the activation of lymphocytic responses such as IL-2 secretion and cell migration. These results demonstrated that off-target inhibition of STK10 by erlotinib enhances lymphocytic responses, which lead to the aggravation of skin inflammation.