EGFR酪氨酸激酶抑制剂 (TKIs) 作为EGFR突变阳性晚期非小细胞肺癌 (NSCLC) 患者的一线治疗方案，可有效延长患者的生存时间。然而，其无可避免的耐药现象成为进一步提高靶向药物疗效的瓶颈，目前其获得性耐药产生的机制仍未完全明确。申请人在研究中发现吉非替尼诱导耐药的NSCLC细胞中ErbB4和PDGF的表达水平显著增高，且吉非替尼对耐药细胞ErbB4和Akt磷酸化的抑制作用明显弱于敏感细胞。敏感细胞用PDGF诱导后，吉非替尼对其EGFR、ErbB4和Akt磷酸化的抑制作用均减弱。基于此我们推测ErbB4和PDGF交互作用，可能共同调控NSCLC细胞EGFR-TKIs获得性耐药的产生。本研究拟对ErbB4及PDGF过表达旁路活化EGFR下游信号通路，导致NSCLC细胞获得性耐药的调控机制进行探讨，并鉴定其能否成为有效预测靶向治疗疗效和指导选择NSCLC治疗方案的分子学标志。

In advanced NSCLC patients harboring EGFR mutations, the use of EGFR-TKIs as first-line treatment has provided an unusually large progression-free survival (PFS) benefit. Despite their ability to induce dramatic tumor responses with fewer side effects, the effectiveness of targeted therapies is currently limited because the majority of patients using these agents develop resistance over time, resulting in a relapse or worsening of the cancer. The key to unlocking the true potential of targeted therapies is unveiling molecular mechanisms behind drug resistance. The applicant found that the expression level of ErbB4 and PDGF were significantly higher in gefitinib-resistant NSCLC cells than that in parental sensitive cells. Further studies have shown that gefitinib effectively blocked ErbB4 and Akt phosphorylation in parental sensitive NSCLC cells, while it was less effective in gefitinib-resistant NSCLC cells. Moreover, PDGF treatment markedly diminished its capacity to inhibit phosphorylation of EGFR, ErbB4 and Akt. In this study, we address the hypothesis that ErbB4-PDGF interactions are associated with acquired resistance to EGFR-TKIs. Overall, the molecular mechanisms for the regulation of ErbB4- and PDGF-mediated EGFR-TKIs resistance in NSCLC will be examined, to determine its role in predicting the efficacy of targeted therapy as an effective biomarker.