Mechanisms of tumor resistance to anti-HER/ErbB therapeutics

肿瘤对抗 HER/ErbB 治疗的耐药机制

• 批准号: 7466654
• 负责人: Zhen Fan
• 金额: $ 31.96万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-02 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7466654
• 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; 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; Numbers; Patients; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Play; Production; Protein Overexpression; Public Health; Rate; Receptor Activation; Receptor Cell; Receptor Signaling; Recombinants; Relapse; Renal Tissue; Research; Resistance; Retinal; Risk; Roche brand of trastuzumab; Role; STAT protein; Signal Pathway; Signal Transduction; Specimen; Standards of Weights and Measures; Testing; Therapeutic; Thinking; Tissues; Trastuzumab; Treatment-Related Cancer; Tyrosine; Validation; Xenograft procedure; autocrine; base; cancer cell; chemotherapy; clinically relevant; cytokine; exposed human population; malignant breast neoplasm; member; novel; paracrine; prevent; receptor; receptor expression; recombinant human erythropoietin; response; src Homology Region 2 Domain; tumor

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（由申请人提供）：曲妥珠单抗（赫赛汀）是一种人源化抗her2单克隆抗体，已被证明在her2过表达乳腺癌的标准化疗中添加曲妥珠单抗可获得明显的生存益处。然而，不幸的是，只有30-40%的her2阳性乳腺肿瘤对曲妥珠单抗有反应。在这项提议中，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中发挥作用。促红细胞生成素是一种主要的造血细胞因子，主要由肾中的一组特化细胞产生，作用于骨髓中的红细胞祖细胞，导致红细胞生成。重组人促生成素（rHuEPO）常用于癌症患者，以预防和缓解癌症和癌症治疗相关的贫血和疲劳。最近的研究表明，通过激活非造血组织中的EPO受体（EpoR）， EPO在这些组织中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，尤其是乳腺癌患者的肿瘤标本中。作为I型细胞因子受体家族的一员，EpoR在EPO结合后进行二聚，触发受体相关激酶Jak2的激活，随后触发STAT5的磷酸化，以及由SH2结构域适配器介导的信号转导级联反应，该信号转导级联反应与her2介导的信号通路有很大的重叠。我们在初步研究中发现，EpoR与HER2在大量已建立的乳腺癌细胞系和患者的乳腺癌组织标本中共表达。乳腺癌细胞暴露于rHuEPO以EpoR表达依赖的方式激活细胞信号，并且曲妥珠单抗和rHuEPO同时治疗HER2/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。我们假设同时给予rHuEPO的细胞信号反应构成了乳腺癌对曲妥珠单抗耐药的临床相关机制。我们计划在四个方面验证这一假设：1)在HER2/EpoR双阳性乳腺癌细胞中证实rHuEPO对曲妥珠单抗的细胞保护作用；2)确定同时给药rHuEPO在多大程度上抵消了曲妥珠单抗在HER2/EpoR双阳性乳腺癌异种移植中的抗肿瘤活性；3)阐明EpoR下游信号通路，rHuEPO通过激活该通路介导抗曲妥珠单抗的细胞保护作用；4)确认HER2和EpoR在乳腺癌患者肿瘤标本中共表达并确定其频率。这些目标的实现将揭示EPO/EpoR信号是否有助于曲妥珠单抗耐药。阳性结果将支持进一步研究rHuEPO是否应继续与曲妥珠单抗同时应用于乳腺癌患者。