Mechanisms of Herceptin resistance

描述（申请人提供）：her 2基因在约30%的转移性乳腺癌中过表达，与疾病快速进展和总生存期降低相关。对HER 2靶向药物赫赛汀的中位反应持续时间不到一年，表明获得性耐药是治疗HER 2过表达转移性乳腺癌的主要临床问题。本申请的长期目标是确定赫赛汀耐药的机制和预测因子，以提高HER 2过表达乳腺癌患者的生存率。赫赛汀耐药细胞表达降低水平的细胞周期蛋白依赖性激酶（cdk）抑制剂p27，并显示胰岛素样生长因子-I受体（IGF-IR）、HER 2和HER 3之间的独特受体串扰。我们的中心假设是IGF-IR/HER 2/HER 3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HER 2过表达乳腺癌细胞增殖增加。使用结合纳米技术、遗传学和药理学的特别创新的多学科方法，我们将确定（1）在获得性赫赛汀耐药中p27下调的机制，（2）IGF-IR/HER 2/HER 3受体复合物在获得性赫赛汀耐药中的作用，以及（3）IGF-IR、HER 3和FAK是否是改善对赫赛汀反应的体内靶点。获得性赫赛汀耐药的多个模型和多个患者肿瘤组织集使我们处于独特的位置，以发现新的治疗靶点和耐药标志物。最终，这项研究将通过确定新的分子靶点，新型药物组合和HER 2过表达乳腺癌耐药的分子标志物来造福人类健康。了解导致获得性赫赛汀耐药的机制将最终导致完善的治疗策略和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.