Her2阳性和PIK3CA突变共存型乳腺癌分子靶向治疗机制的研究

HER2-positive breast cancer is highly aggressive and has a higher risk of recurrence and metastasis. Drug resistance remains a big challenge to HER2-targeted cancer therapy. Strikingly, at least 40% of HER2-positive breast cancers carry PIK3CA hotspot mutations, a condition which is often associated with drug resistance and poor clinical outcome. Thus, there is an urgent need to search for druggable molecular targets for effective treatment of this malignant disease. Our previous work in an inducible transgenic mouse model has demonstrated that the oncogenic mutation PIK3CAH1047R plays an important role in the initiation and maintenance of breast cancer and that inhibitors targeting PI3K have significant inhibitory effects on the growth of mammary tumors that are dependent on the PI3K pathway activation (Nature Medicine, 2011). Here we propose to establish a complex transgenic mouse model of breast cancer that mimics the clinical situation of HER2-positive breast cancer patients carrying a coexisting PIK3CAH1047R mutation. We will use this mouse model to interrogate the impact of PIK3CAH1047R on the initiation and maintenance of HER2-positive breast cancer. In combined with humanized mouse models of breast cancer, we will evaluate the anti-tumor effects of PI3K inhibitors as a single agent or in combined with HER2-directed therapy, identify and validate molecular driver events that are responsible for drug resistance. The long-term goal of this project is to define effective treatment strategies for HER2-positive breast cancer and improve patients' survival.

HER2阳性乳腺癌恶性程度高,复发和转移早。耐药性仍是HER2分子靶向治疗的瓶颈。临床研究发现至少40%HER2阳性乳腺癌中存在PIK3CA基因突变，并与靶向治疗的耐药性和不良预后有关。因此深入阐明此类乳腺癌的分子发病机制，寻找可用作药物靶分子的关键变异基因是治愈这种疾病的根本途径。申请人前期利用转基因小鼠模型研究发现PIK3CA基因突变在乳腺癌发生、发展和维系中起关键作用，PI3K靶向抑制剂对依赖PI3K信号传导通路的乳腺癌有显著疗效（Nature Medicine, 2011）。在此基础上，申请人成功构建了HER2阳性和PIK3CA突变共存型乳腺癌转基因小鼠模型，拟以此为平台研究此类乳腺癌发生发展的分子机制、探索以PI3K作为单一靶向或与HER2联合靶向治疗的可行性及可能产生的耐药性、寻找针对此类HER2阳性乳腺癌更有效的药物靶分子，为防止复发和治愈此类乳腺癌提供新思路。

肿瘤靶向药物的耐药性是影响治疗成败的主要原因，HER2阳性乳腺癌靶向治疗中，HER2受体下游PI3K信号通路的异常激活是导致靶向治疗失败的一个重要因素。临床中多达40%的乳腺癌患者存在有PI3K激活突变。本项目成功地建立了HER2阳性和PI3K激活突变共存型转基因小鼠（MMTV-Her2-iPIK3CAH1047R）转基因小鼠乳腺肿瘤模型，用以模拟临床中HER2阳性和PIK3CAH1047R突变共存型乳腺癌的发生和发展，并以此模型为基础，研究了这类肿瘤复发的机理和治疗方案的选择。非常有意义的是在临床乳腺癌患者中发现并鉴定了PIK3CAC420R突变的出现可导致HER2靶向治疗耐药，而HER小分子靶向抑制剂Lapatinib与PI3K抑制剂联用则可克服此耐药性。在研究乳腺癌靶向治疗的过程中，我们意外发现PI3K抑制剂和PARP抑制剂联合应用也能够有效治疗卵巢癌。此外，我们还利用差向富集／免疫荧光原位杂交技术从乳腺癌脑膜转移临床患者的脑脊液中对肿瘤细胞进行动态检测、体外培养及以2代测序结果分析为基础的药敏实验，对乳腺癌患者脑膜转移的诊断和治疗有十分重要临床指导意义。