LRIG2调控RTK信号通路介导胶质瘤EGFR酪氨酸激酶抑制剂耐药的研究

Overexpression and mutation of EGFR occurs in more than 50% of patients with glioblastoma, however, the therapeutic effect of EGFR tyrosine kinase inhibitor (EGFR-TKI) on glioblastomas is invariably limited. The drug resistance of EGFR-TKI is associated with the activation of the redundant receptor tyrosine kinases (redundant RTKs), the mechanisms remain largely unknown. Our preliminary data has demonstrated that LRIG2 exerts as a tumour promoter to enhance the malignant biological characteristics of glioma through regulation of multiple RTKs. LRIG2 is found to correlate strongly with the drug resistance of EGFR-TKI in glioma. EGFR-TKI inhibits the activation of EGFR, while simutaneously LRIG2 enhances the activation of c-Met and downstream pathways of RTKs. We hypothesize that LRIG2 contributes to the drug resistance of EGFR-TKI through regulation of redundant RTK signaling pathway. We proposed three main aims: 1) To find out the correlation of LRIG2 and EGFR-TKI drug resistance; 2) To explore the mechanisms of which LRIG2 regulates the pathways of redundant RTKs; 3) To demonstrate whether LRIG2 involves in effecting the EGFR-TKI associated biological characteristics of glioma, the findings will contribute to the revelation of the mechanism of EGFR-TKI resistance and improve the treatment efficiency in glioma.

50%以上胶质母细胞瘤中存在EGFR过表达或突变，但EGFR酪氨酸激酶抑制剂（EGFR-TKI）对胶质母细胞瘤疗效不佳。胶质瘤EGFR-TKI耐药被认为与冗余RTKs (redundant RTKs)代偿激活相关，其机制尚不清楚。课题申请人证实LRIG2在胶质瘤中为癌基因，为多RTK调控蛋白，影响胶质瘤多种生物学特性，后续研究发现LRIG2与胶质瘤EGFR-TKI耐药关系密切。EGFR-TKI虽可抑制胶质瘤细胞中EGFR磷酸化，但LRIG2可导致磷酸化c-Met及RTK下游信号蛋白升高，我们推测LRIG2调控冗余RTK信号通路介导胶质瘤EGFR-TKI耐药。本课题拟通过体内外实验，研究LRIG2表达与EGFR-TKI耐药关系，LRIG2调控冗余RTK信号通路的机制及对胶质瘤EGFR-TKI耐药相关生物学特性的影响。上述研究结果将有助于阐明胶质瘤EGFR-TKI耐药机制，改善胶质瘤治疗效果。

项目背景：胶质母细胞瘤（glioblastoma, GBM）是成人最常见的颅内肿瘤，也是人类肿瘤中致死性最高的肿瘤之一。即使给予积极的综合治疗（如手术，放疗和化疗），平均生存时间仅为 12-15 个月，从而迫切需要找到一种新的药物来改善 GBM 患者的预后。由于 50%以上 GBM 均存在表皮生长因子受体（epidermal growth factor receptor，EGFR）突变或过表达，EGFR 高表达预示 GBM患者预后差。人们对 EGFR酪氨酸激酶抑制剂（tyrosine kinase inhibitor, TKI）在改善胶质瘤的预后上寄予厚望，但令人遗憾的是，多数 GBM 患者对于 EGFR-TKI 耐药。因此，胶质瘤 EGFR-TKI 耐药机制为目前研究的热点。.主要研究内容：在使用EGFR抑制剂吉非替尼（Gefitinb）治疗胶质瘤时，LRIG2代偿性激活调控冗余的RTK（如AXL）及其下游信号分子。.重要结果：吉非替尼（Gefitinb）治疗胶质瘤时，诱导LRIG2表达上调，LRIG2代偿性激活调控AXL及其下游信号分子，从而导致胶质瘤抵抗吉非替尼。.科学意义：本研究揭示胶质瘤对EGFR抑制剂耐药的机制，为胶质瘤的治疗提供重要的理论依据。