erbB2/erbB3/IGF-1R异源三聚体在介导erbB2靶向治疗耐药中的作用及其机制研究

Amplification and/or overexpression of erbB2 (or HER2/neu) occur in approximately 20-30% of invasive breast cancer and are significantly associated with a worse prognosis for breast cancer patients. ErbB2 is an attractive therapeutic target for the treatment of erbB2 addicted tumors. However, both primary and acquired resistances to trastuzumab and lapatinib are common and currently represent a significant clinical problem. To elucidate the mechanisms of acquired resistance to erbB2-targeted therapies is of critical importance. In our previous study, we have demonstrated that erbB2 simultaneously interacted with erbB3 and IGF-1R to form a trimeric complex, which activated PI-3K/Akt signaling and Src kinase and then leads to trastuzumab resistance. In this project, we will elucidate the possible mechanism of the formation of trimeric complex. And we intend to develop a proper technique to detect the trimer in patent samples to predict the sensitivity of targeted therapy. Furthermore, we also detect the possible role of the trimer in the sensitivity to lapatinib, another targeted erbB2 agent. This will not only provide the direction to develop novel therapeutic strategies/agents but also shed light on reliable biomarkers to predict the efficacy of erbB2-targeted therapies.

20-30%乳腺癌病人存在erbB2基因扩增或过表达，erbB2与病情发展转归密切相关，是很好的治疗靶点，然而erbB2靶向治疗药物原发和继发耐受是erbB2阳性乳腺癌治疗的一个重大难题，揭示其耐药机制对改善患者预后十分必要。本课题组前期发现erbB2、erbB3、IGF-1R两两相互结合形成异源三聚体活化PI-3K/Akt 信号通路和Src激酶，最终导致trastuzmab耐药。本项目基于此，进一步揭示erbB2/erbB3/IGF-1R异源三聚体形成的可能机制，探寻可用于临床标本中三聚体检测的新技术，由此可预判靶向药物治疗的敏感性。同时拟探讨三聚体对另一erbB2靶向药物lapatinib敏感性的可能影响及机制。该研究成果将对指导临床治疗产生深远影响，不仅提供预测靶向药物敏感性的分子标志，而且还为个体化临床治疗提供理论依据及指导，大大改善erbB2阳性乳腺癌患者预后。

ErbB2靶向治疗药物原发性和获得性耐受是erbB2阳性乳腺癌治疗中亟待解决的重大难题。本课题组前期研究发现erbB2、erbB3、IGF-1R两两相互结合形成异源三聚体（erbB2/erbB3/IGF-1R）导致trastuzumab耐药。本项目在此基础上进行了深入研究和拓展，揭示了erbB3配体HRG及IGF-1R配体IGF-II增多是促使erbB2、erbB3、IGF-1R形成三聚体的原因之一。同时本研究还发现erbB2/erbB3/IGF-1R三聚体的形成使肿瘤细胞对另一erbB2靶向药物lapatini的敏感性也下降，进一步分析具体作用机制发现异源三聚体中的erbB3主要通过激活p-AKT同时介导了Trastuzumab和lapatinib的耐药。与其不同的是IGF-1R主要通过活化p-Src参与了细胞对Trastuzumab的耐受而并不影响对lapatinib的敏感性。鉴于erbb3在erbb2靶向治疗耐药中的重要作用，本课题组自主研发了特异性针对erbb3的抗体，并取得初步成效，并且课题组进一步深入研究了erbB3信号通路在参与耐药形成中的具体作用，研究结果显示，erbB3通过抑制miR-203和miR-542-3p表达而上调survivin的表达。该研究成果将对指导临床治疗产生深远影响，不仅可提供预测靶向药物敏感性的分子标志，而且还为个体化临床治疗提供理论依据及指导，大大改善erbB2阳性乳腺癌患者预后。