Liu Feiyang, Zou Fengming, Chen Cheng, Yu Kailin, Liu Xiaochuan, Qi Shuang, Wu Jiaxin, Hu Chen, Hu Zhenquan, Liu Juan, Liu Xuesong, Wang Li, Ge Juan, Wang Wenchao, Ren Tao, Bai Mingfeng, Cai Yujiao, Xiao Xudong, Qian Feng, Tang Jun, Liu Qingsong, Liu Jing
High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, P. R. China Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, P. R. China.
High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, P. R. China University of Science and Technology of China, Hefei, Anhui, P. R. China.
Ther Adv Med Oncol. 2019 May 17;11:1758835919849757. doi: 10.1177/1758835919849757. eCollection 2019.
cKIT kinase overexpression and gain-of-function mutations are the critical pathogenesis of gastrointestinal stromal tumors (GISTs). Although the multiple kinase inhibitors such as imatinib, sunitinib, and regorafenib have been approved for GISTs, the acquisition of polyclonal secondary resistance mutations in KIT is still a limitation for GIST treatment. Here we explored the KIT inhibitory activity of axitinib in preclinical models and describe initial characterization of its activity in GIST patient-derived primary cells.
The activities of axitinib against mutant KIT were evaluated using protein-based assay and a panel of engineered and GIST-derived cell lines. The binding modes of axitinib-KIT/KIT mutants were analyzed. Four primary cells derived from GIST patients were also used to assess the drug response of axitinib.
Axitinib exhibited potent activities against a variety of cKIT associated primary and secondary mutations. It displayed better activity against cKIT wild-type, cKIT V559D/A/G, and L576P primary gain-of-function mutations than imatinib, sunitinib, and regorafenib. In addition, it could inhibit imatinib resistant cKIT T670I and V654A mutants and GIST preclinical models.
Our results provide the basis for extending the application of axitinib to GISTs patients who are unresponsive or intolerant to the current therapies.
cKIT激酶过表达和功能获得性突变是胃肠道间质瘤（GIST）的关键发病机制。尽管多种激酶抑制剂如伊马替尼、舒尼替尼和瑞戈非尼已被批准用于治疗GIST，但KIT中多克隆继发性耐药突变的出现仍是GIST治疗的一个局限。在此，我们在临床前模型中探究了阿昔替尼对KIT的抑制活性，并描述了其在GIST患者来源的原代细胞中的活性初步特征。
使用基于蛋白质的检测方法以及一组工程化细胞系和GIST来源的细胞系评估阿昔替尼对突变型KIT的活性。分析阿昔替尼与KIT/KIT突变体的结合模式。还使用了4例来自GIST患者的原代细胞来评估阿昔替尼的药物反应。
阿昔替尼对多种与cKIT相关的原发性和继发性突变均表现出强效活性。与伊马替尼、舒尼替尼和瑞戈非尼相比，它对cKIT野生型、cKIT V559D/A/G和L576P原发性功能获得性突变表现出更好的活性。此外，它能够抑制伊马替尼耐药的cKIT T670I和V654A突变体以及GIST临床前模型。
我们的结果为将阿昔替尼的应用扩展至对当前治疗无反应或不耐受的GIST患者提供了依据。
