A431鳞状细胞异种移植瘤模型中c-Kit信号通路诱导其对EGFRIs耐药机制的影响  

Acquired Resistance to EGFR Tyrosine Kinase Inhibitor in A431 Squamous Cell Carcinoma Xenografts is Mediated by c-Kit Pathway

作　　者：张丽霞[1] 杨晓鲲[2] 王倩[1] 赵蓓[1] 蔡震[3] 

机构地区：[1]四川省医学科学院四川省人民医院皮肤性病研究所,四川成都610072 [2]成都军区总医院急诊科,四川成都610083 [3]四川省医学科学院四川省人民医院整形外科,四川成都610072

出　　处：《中国皮肤性病学杂志》2016年第12期1214-1218,1251,共6页The Chinese Journal of Dermatovenereology

基　　金：四川省科技厅课题基金支持(3JC0511)

摘　　要：目的建立EGFRIs(吉非替尼)耐药的EGFR野生型移植瘤模型,并研究其可能耐药机制。方法雌性BALB/c裸鼠皮下注射A431细胞,肿瘤生长到150×200mm^3,口服给予50mg/kg的吉非替尼,1次/d,连续25周后对EGFRIs产生耐药。比较敏感和耐药移植瘤的全基因组基因表达谱寻找目的基因。耐药模型分别接受空白对照组、吉非替尼、目的基因抑制剂(AMG706),或它们的混合物治疗21d,检测肿瘤组织生长、细胞凋亡、目的基因以及相关细胞因子表达情况。结果 C-kit在吉非替尼耐药的A431异种移植瘤中过表达,双重阻断EGFR和c-Kit信号有协同作用,引起细胞凋亡。结论 A431异种移植瘤模型中诱导的吉非替尼耐药可能与c-Kit过表达有关。EGFRIs和c-Kit抑制剂的联合治疗可能阻断这种耐药机制,抑制肿瘤细胞生长。Objective To establish the wild type EGFR xenograft model with EGFRIs（gefitinib）-resistant, and to study the possible mechanism of drug resistance. Methods A431 cells were subcutaneously injected to female athymic BALB/c nude mice. When tumor grew up to 150 - 200mm^3, mice were treated with oral gefitinib （50 mg/kg） once daily. The resistance to EGFRIs（gefitinib） developed following approximately 25 weeks of gefitinib treatment. The Gene Chip Human Genome SNP 6. 0 and U133 plus 2. 0 arrays were used to analyze the genomic gene copy number and gene expression in gefitinib-sensitive and resistant A431 tumors. Mice were randomly divided into four groups, including blank, gefitinib, target gene inhibitor （AMG706）, and their combination after 21 days of treatment. Tumor growth, cell apoptosis, the expression of target gene and related cytokines were detected. Results C-Kit was over-expressed in the gefitinib-resistant A431 xenografts, and blockade of both EGFR and c-Kit signaling induced cell apoptosis. Conclusion Gefitinib resistance induced in the A431 xenograft mouse model is possibly associated with over-expression of c-Kit. Combination of EGFRIs and c-Kit inhibitor could abolish resistance and inhibit tumor cell growth.

关 键 词：表皮生长因子受体(EGFR) A431 C-KIT 鳞状细胞癌 

分 类 号：R739.5[医药卫生—肿瘤]