酪氨酸激酶抑制剂伊马替尼是治疗胃肠道间质瘤（gastrointestinal stromal tumor, GIST）的主要药物之一，然而部分患者服用伊马替尼后会出现严重的心脏毒性，其发生机制尚不十分清楚。目前研究认为，内质网应激介导的不同信号转导通路在伊马替尼致心脏毒性中发挥了重要作用，而这些信号通路又通过c-Abl与线粒体信号通路发生作用。伊马替尼竞争性结合酪氨酸激酶区ATP结合位点，引起心肌细胞能量代谢异常，增加了氧化应激，使c-Abl表达及PDGFR磷酸化异常，而c-Abl和PDGFR介导的信号转导通路异常与伊马替尼心脏毒性的发生密切相关。

Imatinib, a tyrosine kinase inhibitor, is one of the major drugs for treating gastrointestinal stromal tumor (GIST). However, some patients suffer severe cardiotoxicity after imatinib treatment, with unclear mechanism. Studies have suggested that the different signal transduction pathways mediated by the endoplasmic reticulum stress play a central role in imatinib-induced cardiactoxicity, and these signal pathways can interact with the mitochondrial signal pathway through c-Abl. Competitive binding of imatinib to the ATP binding site in tyrosine kinase domain cause abnormal myocardial energy metabolism and increase oxidative stress, and the sustained oxidative stress lead to abnormal expression of c-Abl and phosphorylation of PDGFR, meanwhile, c-Abl and PDGFR-mediated signal transduction pathway abnormalities is closely associated with imatinib induced cardiotoxicity.

上海市重点学科建设项目资助(No. B905)