Mechanisms of Herceptin resistance

描述（由申请人提供）：her2基因在大约30%的转移性乳腺癌中过表达，并且与疾病快速进展和总生存期降低相关。her2靶向药物赫赛汀（Herceptin）的应答中位持续时间不到一年，这表明获得性耐药是治疗her2过表达转移性乳腺癌的主要临床问题。这项应用的长期目标是确定赫赛汀耐药的机制和预测因素，以提高her2过表达乳腺癌患者的生存率。赫赛汀耐药细胞表达细胞周期蛋白依赖性激酶（cdk）抑制剂p27水平降低，并在胰岛素样生长因子- 1受体（IGF-IR）、HER2和HER3之间表现出独特的受体交叉对话。我们的中心假设是IGF-IR/HER2/HER3复合物激活下游激酶信号通路，促进p27的磷酸化和降解，导致HER2过表达的乳腺癌细胞增殖增加。采用一种特别创新的多学科方法，结合纳米技术、遗传学和药理学，我们将确定(1)p27在获得性赫赛汀耐药中下调的机制，(2)IGF-IR/HER2/HER3受体复合物在获得性赫赛汀耐药中的作用，以及(3)IGF-IR、HER3和FAK是否是改善赫赛汀应答的体内靶点。获得性赫赛汀耐药的多种模型和多种患者肿瘤组织集使我们处于发现新的治疗靶点和耐药标记的独特位置。最终，该研究将通过确定her2过表达乳腺癌的新分子靶点、新药物组合和耐药分子标记，造福人类健康。了解导致获得性赫赛汀耐药的机制将最终导致改进治疗策略并提高乳腺癌患者的生存率。

DESCRIPTION (provided by applicant): The her2 gene is overexpressed in approximately 30% of metastatic breast cancers, and is associated with rapid disease progression and reduced overall survival. The median duration of response to the HER2-targeted drug Herceptin is less than one year, indicating that acquired drug resistance is a major clinical problem in the treatment of HER2-overexpressing metastatic breast cancer. The long-term goal of this application is to identify mechanisms and predictors of Herceptin resistance in order to improve the survival of patients with HER2-overexpressing breast cancer. Herceptin-resistant cells express reduced levels of the cyclin-dependent kinase (cdk) inhibitor p27 and show a unique receptor cross-talk between insulin-like growth factor-I receptor (IGF-IR), HER2, and HER3. Our central hypothesis is that the IGF-IR/HER2/HER3 complex activates downstream kinase signaling pathways that promote phosphorylation and degradation of p27, causing increased proliferation of HER2-overexpressing breast cancer cells. Using a particularly innovative multidisciplinary approach that combines nanotechnology, genetics, and pharmacology, we will determine (1) the mechanisms by which p27 is down- regulated in acquired Herceptin resistance, (2) the role of the IGF-IR/HER2/HER3 receptor complex in acquired Herceptin resistance, and (3) if IGF-IR, HER3, and FAK are in vivo targets for improving response to Herceptin. Access to multiple models of acquired Herceptin resistance and multiple patient tumor tissue sets places us in a unique position to discover novel therapeutic targets and markers of resistance. Ultimately, this study will benefit human health by identifying new molecular targets, novel drug combinations, and molecular markers of drug resistance in HER2-overexpressing breast cancer. Understanding the mechanisms leading to acquired Herceptin resistance will ultimately lead to refined therapeutic strategies and improved survival rates for patients with breast cancer.