酪氨酸激酶抑制剂（TKI）继发耐药是肺癌靶向治疗失败的主要原因，是当前肿瘤学研究热点和难点。我们前期发现谷胱甘肽S-转移酶pi（GSTpi）在TKI继发耐药肺癌临床样本和耐药细胞株H827/GR中核内水平显著升高。下调核内GSTpi蛋白水平显著促进H827/GR的凋亡，但分子机制不清。为了阐明GSTpi是否通过核内转运参与耐药细胞的抗凋亡的分子机制，本项目拟以吉非替尼耐药的人NSCLC为模型，从细胞水平和移植瘤模型评价下调GSTpi及抑制其入核对耐药细胞的凋亡和增殖影响。基于前期我们发现GSTpi 可以与介导凋亡的重要转录因子c-Jun结合，我们将重点研究，GSTpi通过入核调控c-Jun的转录活性而调节耐药细胞株的抗凋亡，最终促进耐药NSCLC增殖的分子机制。最后，本研究拟结合临床样本评价核内GSTpi水平与临床疗效和预后的关系，这将为克服肺癌TKI继发耐药提供潜在新靶标。

The failure of targeting therapy with Tyrosine kinase inhibitor (TKI) on NSCLC is mainly due to the acquired resistance, but the mechanisms remain unknown. Our previous work demonstrated that Glutathione S-transferases pi (GSTpi) is highly localized in the nucleus of tissue specimens of patients with acquired resistance to tyrosine kinase inhibitors (TKIs) and in established Gefitinib resistant H827/GR cells. We further showed that knockdown of GSTpi in the nucleus of H827/GR significantly induced cell apoptosis and decreased cell proliferation. However, it remain unknown how GSTpi can be translocated into nucleus and inhibit apoptosis. In order to understand the underlying molecular mechanism, we will first investigate if knockdown of GSTpi or inhibition of its nuclear translocation in H827/GR cells can decrease cell proliferation and induce apoptosis both in cells and mouse xenograft model. Based on our preliminary result that GSTpi can bind to c-Jun, an important transcription factor regulating cell apoptosis and proliferation, we will focus on addressing how GSTpi is translocated into nucleus to mediate c-Jun transcription activity in regulating cell apoptosis. Lastly, we will assess the relationship between the levels of nuclear GSTpi and the TKI therapeutic effects and prognosis in clinical specimens. This study will offer a new therapeutic target to overcome the drug-resistance to TKI in NSCLC.