CAS Key Laboratory of Tissue Microenvironment and Tumor, SINH-Changzheng Hospital Joint Center for Translational Medicine, Institutes for Translational Medicine (CAS-SMMU), Changzheng Hospital, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, People's Republic of China.
Department of General Surgery, PLA General Hospital, Beijing, People's Republic of China.
Gastric Cancer. 2020 Sep;23(5):837-847. doi: 10.1007/s10120-020-01069-1. Epub 2020 Apr 6.
The majority of GISTs express mutationally activated KIT. Imatinib and sunitinib are approved KIT-inhibiting therapies. Their efficacy is usually hampered by the acquired multiple secondary drug-resistance KIT mutations. The most problematic resistance subset is GISTs with acquisition of secondary mutations in the KIT activation loop. Here, we establish the spectrum of activity of dasatinib against a comprehensive collection of clinically relevant KIT mutants associated with drug-sensitive and drug-resistant GIST.
The cellular and in vitro activities of tyrosine kinase inhibitors (TKIs) against mutant KIT were assessed using a panel of engineered and GIST-derived cell lines. The in vivo activities of dasatinib were determined using TKI-resistant xenograft models.
In engineered and GIST-derived cell lines, dasatinib potently inhibited KIT with primary mutations in exon 11 or 9 and a range of secondary imatinib-resistant mutations in exons 13 and 14, encoding the ATP-binding pocket, and in exons 17 and 18, encoding the activation loop, with the exception of a substitution at codon T670. Our data show that dasatinib is more potent than imatinib or sunitinib at inhibiting the activity of drug-resistant KIT mutants. Dasatinib also induces regression in GIST-derived xenograft models containing these secondary mutations. A major determinant of the efficacy of dasatinib for the treatment of advanced GIST is the activity of this inhibitor against KIT mutants.
Dasatinib shows efficacy in cancer models, inhibiting a wide range of oncogenic primary and drug-resistant KIT mutants. These results have implications for the further development of dasatinib precision therapy in GIST patients.
大多数 GIST 表达突变激活的 KIT。伊马替尼和舒尼替尼是批准的 KIT 抑制疗法。它们的疗效通常受到获得的多种继发性药物耐药性 KIT 突变的阻碍。最成问题的耐药亚组是获得 KIT 激活环继发性突变的 GIST。在这里，我们建立了达沙替尼对与药物敏感和耐药 GIST 相关的综合临床相关 KIT 突变体的活性谱。
使用一组工程化和 GIST 衍生的细胞系评估酪氨酸激酶抑制剂 (TKI) 对突变 KIT 的细胞和体外活性。使用 TKI 耐药异种移植模型确定达沙替尼的体内活性。
在工程化和 GIST 衍生的细胞系中，达沙替尼对 11 号或 9 号外显子中的原发性突变和 13 号和 14 号外显子中编码 ATP 结合口袋的一系列继发性伊马替尼耐药突变，以及 17 号和 18 号外显子中编码激活环的突变具有很强的抑制作用，除了密码子 T670 的取代。我们的数据表明，达沙替尼比伊马替尼或舒尼替尼更能抑制耐药 KIT 突变体的活性。达沙替尼还诱导包含这些继发性突变的 GIST 衍生异种移植模型的消退。达沙替尼治疗晚期 GIST 的疗效的主要决定因素是该抑制剂对 KIT 突变体的活性。
达沙替尼在癌症模型中显示出疗效，抑制广泛的致癌原性原发性和耐药性 KIT 突变体。这些结果对进一步开发达沙替尼在 GIST 患者中的精准治疗具有重要意义。
