Off-Target Serine/Threonine Kinase 10 Inhibition by Erlotinib Enhances Lymphocytic Activity Leading to Severe Skin Disorders
Off-Target Serine/Threonine Kinase 10 Inhibition by Erlotinib Enhances Lymphocytic Activity Leading to Severe Skin Disorders
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DOI：
10.1124/mol.110.070862
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发表时间：
2011-09-01
影响因子：
3.6
通讯作者：
Suzuki, Hiroshi
中科院分区：
文献类型：
--
作者：
Yamamoto, Naoko;Honma, Masashi;Suzuki, Hiroshi
皮肤病是与表皮生长因子受体（EGFR）激酶抑制剂治疗相关的最常见不良事件之一，其中，已知厄洛替尼引起的皮肤病比该类药物更频繁和更严重。尽管先前的报道表明皮肤表现是由多种EGFR相关的皮肤稳态功能的抑制引发的，但仅此机制不能解释不同激酶抑制剂引起的皮肤疾病的频率和严重程度的差异。在本研究中，我们重点关注了脱靶激酶抑制与皮肤疾病加重之间的关系。基于使用报告的K（d）值和血浆药物浓度的计算，选择丝氨酸/苏氨酸激酶10（STK 10）和Ste 20样激酶（SLK）作为厄洛替尼优先抑制吉非替尼的候选物。体外实验证实，临床浓度的厄洛替尼可抑制STK 10和SLK激酶活性，而吉非替尼仅轻微抑制STK 10。研究还表明，厄洛替尼在临床浓度下上调淋巴细胞反应，如白细胞介素（IL）-2分泌和细胞迁移，而吉非替尼不影响淋巴细胞活性。此外，小干扰RNA实验显示，STK 10在上调厄洛替尼治疗诱导的淋巴细胞反应中起主要作用。最后，使用刺激性超敏反应模型在体内评估了厄洛替尼诱导的淋巴细胞活化的作用。结果表明，厄洛替尼通过激活淋巴细胞反应（如IL-2分泌和细胞迁移）减轻皮肤炎症反应。这些结果表明，厄洛替尼对STK 10的脱靶抑制增强了淋巴细胞反应，这导致皮肤炎症的加重。
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.