Mechanisms of Herceptin resistance

描述(申请人提供)：HER2基因在大约30%的转移性乳腺癌中过度表达，并与疾病快速发展和总存活率降低有关。HER2靶向药物Herceptin的中位缓解期不到一年，这表明获得性耐药是治疗HER2过度表达的转移性乳腺癌的主要临床问题。该应用的长期目标是确定Herceptin耐药的机制和预测因素，以提高HER2过表达乳腺癌患者的存活率。Herceptin耐药细胞表达低水平的细胞周期蛋白依赖性激酶(CDK)抑制物p27，并在胰岛素样生长因子-I受体(IGF-IR)、HER2和HER3之间表现出独特的受体串扰。我们的中心假设是IGF-IR/HER2/HER3复合体激活下游的激酶信号通路，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。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)p27在获得性赫赛汀耐药中下调的机制，(2)IGF-IR/HER2/HER3受体复合体在获得性赫赛汀耐药中的作用，以及(3)IGF-IR、HER3和FAK是否为体内改善对赫赛汀反应的靶点。接触到获得性赫赛汀耐药的多个模型和多个患者肿瘤组织集，使我们处于发现新的治疗靶点和耐药标记的独特地位。最终，这项研究将通过确定新的分子靶点、新的药物组合以及HER2过表达乳腺癌耐药的分子标记来造福人类健康。了解导致获得性赫赛汀耐药的机制将最终导致改进治疗策略和提高乳腺癌患者的存活率。

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.