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Mechanisms of tumor resistance to anti-HER/ErbB therapeutics

肿瘤对抗 HER/ErbB 治疗的耐药机制

基本信息

批准号：
8212508
负责人：
Zhen Fan
金额：
$ 31万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-02 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8212508
关键词：
1-Phosphatidylinositol 3-Kinase Adaptor Signaling Protein Adverse effects Anemia Antineoplastic Agents Binding Binding Sites Bone Marrow Breast Cancer Cell Cancer Cell Growth Cancer Patient Cancer cell line Cardiac Case Study Cell Surface Receptors Cell Survival Cells Cessation of life Clinical Conditioned Culture Media Cytokine Receptors Cytoprotection Docking Epidermal Growth Factor Receptor Erythrocytes Erythroid Progenitor Cells Erythropoiesis Erythropoietin Erythropoietin Receptor Family Fatigue Frequencies Goals Homodimerization Human Interleukin-3 Investigation Janus kinase 2 Kidney Knowledge Laboratories Link MEKs Malignant Neoplasms Mammary Neoplasms Mediating Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases Monoclonal Antibodies Neurons Patients Pharmaceutical Preparations Phosphorylation Phosphotransferases Play Production Receptor Activation Receptor Cell Receptor Signaling Recombinants Relapse Renal Tissue Research Resistance Retinal Roche brand of trastuzumab Role STAT protein Signal Pathway Signal Transduction Specimen Testing Therapeutic Tissues Trastuzumab Treatment-Related Cancer Tyrosine Validation Xenograft procedure autocrine base cancer cell chemotherapy clinically relevant cytokine exposed human population high risk malignant breast neoplasm member novel overexpression paracrine prevent public health relevance receptor receptor expression recombinant human erythropoietin response src Homology Region 2 Domain tumor

项目摘要

DESCRIPTION (provided by applicant): Trastuzumab (Herceptin), a humanized anti-HER2 monoclonal antibody, has been demonstrated to confer a clear survival benefit when it is added to standard chemotherapy for HER2-overexpressing breast cancer. Unfortunately, however, only 30-40% of HER2-positive breast tumors respond to trastuzumab. In this proposal, we will explore whether erythropoietin (EPO)-induced cell signaling plays a role in breast cancer resistance to trastuzumab. EPO is a prime hematopoietic cytokine produced mainly by a group of specialized cells in the kidney and acts on erythroid progenitor cells in the bone marrow, leading to erythropoiesis. Recombinant human EPO (rHuEPO) is frequently used in cancer patients to prevent and alleviate cancer- and cancer treatment-related anemia and fatigue. Recent studies have shown that EPO has remarkable cytoprotective activity in nonhematopoietic tissues via activation of the EPO receptor (EpoR) found in these tissues. Interestingly, EpoR is also present in some clinical tumor specimens, particularly tumor specimens from breast cancer patients. As a member of the type I cytokine receptor family, EpoR homodimerizes upon EPO binding, triggering activation of the receptor-associated kinase Jak2, subsequent phosphorylation of STAT5, and a signal transduction cascade mediated by SH2 domain-containing adaptors that overlaps substantially with HER2-mediated signaling pathways. We found in our preliminary studies that EpoR is co-expressed with HER2 in a significant number of established breast cancer cell lines and breast cancer tissue specimens from patients. Exposure of breast cancer cells to rHuEPO activated cell signaling in an EpoR expression-dependent manner, and concurrent treatment of HER2/EpoR dual-positive breast cancer cells with trastuzumab and rHuEPO reduced the therapeutic response to trastuzumab treatment. We hypothesize that cell signaling in response to concurrent administration of rHuEPO constitutes a clinically relevant mechanism of breast cancer resistance to trastuzumab. We plan to test this hypothesis in four specific aims: 1) to confirm the cytoprotective effect of rHuEPO against trastuzumab in HER2/EpoR dual-positive breast cancer cells; 2) to determine the extent to which concurrent administration of rHuEPO counteracts the antitumor activity of trastuzumab in HER2/EpoR dual-positive breast cancer xenografts; 3) to elucidate the EpoR downstream signaling pathways through activation of which rHuEPO mediates cytoprotection against trastuzumab; and 4) to confirm the presence of HER2 and EpoR co-expression and to determine its frequency in tumor specimens from breast cancer patients. Attainment of these aims will reveal whether EPO/EpoR signaling contributes to trastuzumab resistance. A positive finding will warrant further investigation of whether rHuEPO should continue to be administered concurrently with trastuzumab in breast cancer patients. PUBLIC HEALTH RELEVANCE: The drug erythropoietin (EPO) is often given to breast cancer patients to help prevent or lessen treatment-related anemia and fatigue; however, some evidence from our laboratory and others suggests that EPO might make breast cancer resistant to the anti-breast cancer drug trastuzumab. We will investigate this possibility. Our findings may indicate that EPO should not be administered to breast cancer patients who are being treated with trastuzumab.

描述（由申请方提供）：曲妥珠单抗（赫赛汀）是一种人源化抗HER 2单克隆抗体，已被证明当其添加到HER 2过表达乳腺癌的标准化疗中时可提供明确的生存获益。然而，不幸的是，只有30-40%的HER 2阳性乳腺肿瘤对曲妥珠单抗有反应。在这个提议中，我们将探讨促红细胞生成素（EPO）诱导的细胞信号传导是否在乳腺癌对曲妥珠单抗的耐药性中发挥作用。EPO是主要由肾脏中的一组特化细胞产生的主要造血细胞因子，并作用于骨髓中的红系祖细胞，导致红细胞生成。重组人促红细胞生成素（rHuEPO）经常用于癌症患者，以预防和减轻癌症和癌症治疗相关的贫血和疲劳。最近的研究表明，EPO在非造血组织中通过激活这些组织中发现的EPO受体（EpoR）而具有显著的细胞保护活性。有趣的是，EpoR也存在于一些临床肿瘤标本中，特别是来自乳腺癌患者的肿瘤标本。作为I型细胞因子受体家族的一员，EpoR在EPO结合后同源二聚化，触发受体相关激酶Jak 2的活化，随后STAT 5的磷酸化，以及由含有SH 2结构域的衔接子介导的信号转导级联反应，该衔接子与HER 2介导的信号传导途径基本重叠。我们在初步研究中发现，EpoR与HER 2在大量已建立的乳腺癌细胞系和患者乳腺癌组织标本中共表达。乳腺癌细胞暴露于rHuEPO以EpoR表达依赖性方式激活细胞信号传导，同时用曲妥珠单抗和rHuEPO治疗HER 2/EpoR双阳性乳腺癌细胞降低了对曲妥珠单抗治疗的治疗反应。我们推测，细胞信号传导反应的同时管理的rHuEPO构成了临床相关的机制，乳腺癌耐药曲妥珠单抗。我们计划从四个方面来验证这一假设：1）证实rHuEPO对曲妥珠单抗在HER 2/EpoR双阳性乳腺癌细胞中的细胞保护作用; 2）确定同时给予rHuEPO在HER 2/EpoR双阳性乳腺癌异种移植物中抵消曲妥珠单抗肿瘤活性的程度; 3）阐明EpoR下游信号通路，rHuEPO通过激活EpoR下游信号通路介导抗曲妥珠单抗的细胞保护;和4）确认HER 2和EpoR共表达的存在并确定其在乳腺癌患者的肿瘤样本中的频率。这些目标的实现将揭示EPO/EpoR信号传导是否有助于曲妥珠单抗耐药。一个积极的发现将保证进一步调查是否rHuEPO应继续与曲妥珠单抗同时管理乳腺癌患者。公共卫生相关性：药物促红细胞生成素（EPO）通常用于乳腺癌患者，以帮助预防或减轻治疗相关的贫血和疲劳;然而，我们实验室和其他实验室的一些证据表明，EPO可能使乳腺癌对抗乳腺癌药物曲妥珠单抗产生耐药性。我们将调查这种可能性。我们的研究结果可能表明，EPO不应该用于正在接受曲妥珠单抗治疗的乳腺癌患者。