TY - JOUR T1 - Off-target STK10 inhibition by erlotinib enhances lymphocytic activity leading to severe skin disorders. JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.110.070862 SP - mol.110.070862 AU - Naoko Yamamoto AU - Masashi Honma AU - Hiroshi Suzuki Y1 - 2011/01/01 UR - http://molpharm.aspetjournals.org/content/early/2011/05/23/mol.110.070862.abstract N2 - Skin disorders are among most common adverse events related to treatment with 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 Kd values and plasma drug concentrations, STK10 and 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, while only STK10 is slightly inhibited by gefitinib. It was also shown that erlotinib up-regulated lymphocytic responses such as IL-2 secretion and cell migration at clinical concentrations, while gefitinib did not affect lymphocyte activity. Moreover, siRNA 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. ER -