Molecular determinants underlying herceptin sensitivity and resistance

描述(申请人提供)：赫赛汀/曲妥珠单抗是一种有选择性地针对Her2蛋白的单抗，仍然是Her2阳性乳腺癌的标准治疗药物。然而，曲妥珠单抗改变了阻止癌症进展的生物学过程目前尚不清楚。我们的初步研究结果表明，曲妥珠单抗在培养的乳腺癌细胞和接受辅助治疗的人类患者的肿瘤中都会导致细胞衰老。这种衰老表型与衰老的几个特征有关，包括无法增殖，细胞周期抑制物p16和p21的诱导，衰老相关的β-半乳糖苷酶活性，以及分泌蛋白IGFBP3和Igfbp5的上调。先前的研究表明，胰岛素样生长因子1受体(IGF1R)的高水平表达与曲妥珠单抗的应答率较低有关。与此一致的是，在曲妥珠单抗耐药的乳腺癌细胞中，发现Her2抑制后IGF1R的表达和磷酸化水平升高。重要的是，曲妥珠单抗与选择性IGF1R抑制剂或重组IGFBPs结合可克服曲妥珠单抗的耐药性，导致细胞衰老。总而言之，这些结果揭示了曲妥珠单抗临床疗效的生物学基础，并建议了一种治疗Her2阳性、曲妥珠单抗耐药乳腺癌的实用方法。基于这些新发现，我们提出了以下两个具体目标，以探索区分对曲妥珠单抗敏感和耐药的乳腺癌患者的分子基础。目标1将评估可能控制IGF1R表达水平的几种机制的潜在贡献，这些机制与曲妥珠单抗的敏感性/耐药性相关。目的2将探索酪氨酸激酶受体，除IGF1R外，是否可能参与曲妥珠单抗耐药表型的形成。这些探索性实验的结果将为将来对Her2阳性乳腺癌的这种标准治疗的敏感性和耐受性在机制水平上对分子决定因素进行系统分析奠定基础。

DESCRIPTION (provided by applicant): Herceptin/trastuzumab is a monoclonal antibody that selectively targets the Her2 protein and remains the standard of care for Her2-positive breast cancer. Nevertheless, the biological processes altered by trastuzumab to impede cancer progression are presently unclear. Results from our preliminary studies show that trastuzumab causes cellular senescence in both cultured breast cancer cells and tumors derived from human patients who have undergone treatment in adjuvant therapy. This observed senescent phenotype is associated with several hallmarks of senescence including an inability to proliferate, induction of the cell cycle inhibitors p16 and p21, senescence-associated ?-galactosidase activity, and upregulation of the secreted proteins IGFBP3 and IGFBP5. Previous studies have indicated that high-level expression of the insulin-like growth factor 1 receptor (IGF1R) is associated with a lower response rate to trastuzumab. Consistent with this, elevated levels of IGF1R expression and phosphorylation were found in trastuzumab-resistant breast cancer cells following Her2 inhibition. Importantly, trastuzumab resistance can be overcome by combining trastuzumab with either a selective IGF1R inhibitor or recombinant IGFBPs, resulting in cellular senescence. Collectively, these results reveal the biological underpinnings of trastuzumab's clinical efficacy and suggest a practical approach for the treatment of Her2-positive, trastuzumab-resistant breast cancer. Capitalizing on these new findings, we propose the following two specific aims to explore the molecular basis that distinguish breast cancer patients who are sensitive to trastuzumab from those who are resistant. Aim 1 will assess the potential contributions of several mechanisms that may control the expression level of IGF1R associated with sensitivity/resistance to trastuzumab. Aim 2 will explore whether tyrosine kinase receptors, in addition to IGF1R, could be involved in the development of a trastuzumab-resistant phenotype. Together results from these exploratory experiments will lay the foundation a systemic analysis of molecular determinants at the mechanistic level for sensitivity and resistant to this standard therapy for Her2-positive breast cancer can be conducted in the future.