Multikinase Inhibitors Induce Cutaneous Toxicity through OAT6-Mediated Uptake and MAP3K7-Driven Cell Death.
Multikinase Inhibitors Induce Cutaneous Toxicity through OAT6-Mediated Uptake and MAP3K7-Driven Cell Death.
复制标题
DOI：
10.1158/0008-5472.can-15-0694
复制
发表时间：
2016-01-01
期刊：
影响因子：
11.2
通讯作者：
Baker SD
中科院分区：
文献类型：
--
作者：
Zimmerman EI;Gibson AA;Hu S;Vasilyeva A;Orwick SJ;Du G;Mascara GP;Ong SS;Chen T;Vogel P;Inaba H;Maitland ML;Sparreboom A;Baker SD
在肿瘤学中使用多激酶抑制剂（MKI），如索拉非尼，与称为手足皮肤反应（HFSR）的皮肤不良事件相关，其中压力或摩擦部位发炎和疼痛，从而显著影响生活质量。MKI诱导的HFSR的发病机制尚不清楚，唯一可用的治疗选择包括剂量降低或停止治疗，这对原发性疾病管理有负面影响。为了研究索拉非尼促进角质形成细胞细胞毒性和随后的HFSR诱导的潜在机制，我们在人表皮角质形成细胞中进行了转运蛋白导向的RNAi筛选，并将SLC22A20（OAT6）鉴定为索拉非尼的摄取载体。通过原位激酶组分析对索拉非尼活性的细胞内机制进行进一步研究，发现有丝分裂原活化蛋白激酶MAP 3K7（TEK 1）是索拉非尼诱导细胞死亡的靶点。最后，我们证明索拉非尼在体内诱导角质形成细胞损伤，并且这种作用可以通过与OAT6抑制剂丙磺舒共同治疗来逆转。总的来说，我们的研究结果揭示了一种新的途径，调节一些MKI进入角质形成细胞，并解释了索拉非尼诱导的皮肤毒性的基础，对HFSR的治疗管理具有重要意义。
The use of multi-kinase inhibitors (MKI) in oncology, such as sorafenib, is associated with a cutaneous adverse event called hand-foot skin reaction (HFSR) in which sites of pressure or friction become inflamed and painful, thus significantly impacting quality of life. The pathogenesis of MKI-induced HFSR is unknown, and the only available treatment options involve dose reduction or discontinuation of therapy, which have negative effects on primary disease management. To investigate the underlying mechanisms by which sorafenib promotes keratinocyte cytotoxicity and subsequent HFSR induction, we performed a transporter-directed RNAi screen in human epidermal keratinocytes and identified SLC22A20 (OAT6) as an uptake carrier of sorafenib. Further investigations into the intracellular mechanism of sorafenib activity through in situ kinome profiling identified the mitogen-activated protein kinase MAP3K7 (TAK1) as a target of sorafenib that induces cell death. Finally, we demonstrate that sorafenib induced keratinocyte injury in vivo, and that this effect could be reversed by co-treatment with the OAT6 inhibitor probenecid. Collectively, our findings reveal a novel pathway that regulates the entry of some MKIs into keratinocytes and explains the basis underlying sorafenib-induced skin toxicity, with important implications for the therapeutic management of HFSR.