HER2阳性乳腺癌约占乳腺癌总数的25%,预后较差。Lapatinib作为新的HER2靶向治疗药物，对复发转移性乳腺癌临床疗效显著,但耐药问题严重制约了其临床应用。为了系统研究其耐药性产生的机制，我们建立了具有Lapatinib耐药性的HER2阳性乳腺癌细胞株，利用反相蛋白质芯片技术发现AMPK-mTOR-Autophagy信号通路在Lapatinib耐药细胞株中处于活化状态，而阻断这一信号通路和细胞自噬过程可有效恢复耐药细胞株的药物敏感性，强烈提示该通路在HER2阳性乳腺癌细胞获得Lapatinib耐药性过程中发挥关键作用。本课题拟在此基础上，分别在分子、细胞和动物整体水平进一步阐明该信号通路在HER2阳性乳腺癌细胞获得Lapatinib耐药性过程中的活化原因、作用机制和生物学功能，并探寻可能的干预策略，为有效提高HER2阳性乳腺癌对Lapatinib的治疗敏感性提供新的药物作用靶点。

The HER2 positive breast cancer cells, with poor prognosis, were about 25% of the whole breast cancer patients. Lapatinib was the new receptor tyrosine kinase ihibitor targeting for both EGFR and HER2, which was efficient to treat recurrent and advanced metastatic breast cancer. But the therapeutic efficacy of Lapatinib was seriously limited by the innate and acquired resistance. To uncover the mechanism of acquired resistance to Lapatinib, we firstly established the stable cell lines with acquired resistance of Lapatinib, and found that AMPK-mTOR-Autophagy pathway over-activated in the resistant cells based on RPPA screening strategy. Strikingly, the abrogation of this pathway would recover the susceptability to Lapatinib treatment. These preliminary data suggested that this pathway was crucial for the acquired resistance of Lapatinib in HER2 positive breast cancer cells. Our current project plans to elucidate the potential mechanisms, the detailed function and the biological significance of this signal pathway both in vitro and in vivo. Our work will be much helpful to find novel therapeutic targets to overcome the resistance of Lapatinib in HER2 positive breast cancer cells.