联合抗肿瘤策略：抑制表皮生长因子受体和血管生成

肿瘤的发生和发展与酪氨酸激酶（TK）受体的过表达有关，如表皮生长因子受体（EGFR，ErbB家族）在很多实体瘤中均高表达。体外实验表明，抗EGFR治疗能使肿瘤细胞增殖减弱，抑制细胞生长，但不能使其减少和凋亡；而在体内模型中，抗EGFR治疗导致肿瘤变小，暗示EGFR信号转导影响肿瘤细胞的生物学效应，以及肿瘤一宿主相互作用，如血管生成。     

人体表皮生长因子受体在非小细胞肺癌中表达及意义

有关研究发现人体表皮生长因子受体(HER)家族成员(包括EGFR／HER1／ErbB1、HER2／ErbB2、HER3／ErbB3和HER4／ErbPA)与正常细胞的增殖、分化有关,并且调控肿瘤发生、生长和侵袭。本研究试用免疫组织化学法(IHC),研究该家族成员在非小细胞肺癌中表达及临床意义。     

抗ErbB2抗体曲妥珠单抗的耐药机制与展望

曲妥珠单抗(trastuzumab)在治疗ErbB2高表达的乳腺癌病人中存在耐药现象,对其机制进行研究发现,主要有曲妥珠单抗同ErbB2受体的有效结合受阻、EGFR家族受体和IGF-IR等共表达以及PI3K-AKT信号通路的异常活化等方面。针对这些机制研制了一些可能提高曲妥珠单抗疗效的新型药物。     

表皮生长因子受体家族单克隆抗体耐药机制的研究进展

表皮生长因子受体（EGFR）家族广泛存在于体内各种细胞中,其异常活化与多种人类上皮组织肿瘤的发生、发展密切相关,因此已成为肿瘤治疗的重要靶点之一。目前靶向EGFR家族的药物包括小分子酪氨酸激酶抑制剂和单克隆抗体（简称单抗）类药物,特别是单抗类药物近年来在临床上获得了广泛的应用。但是,越来越多的临床资料表明,大量患者对这类药物表现出原发性耐药或获得性耐药。目前靶向EGFR家族单抗类药物产生耐药的原因主要包括：受体结构改变、血管生成、多种受体酪氨酸激酶的活化、EGFR的亚细胞定位、EGFR下游效应分子的持续激活和EGFR家族生长因子表达的上调等。本文就靶向EGFR家族单抗类药物耐药机制的研究进展进行综述。     

人表皮生长因子受体家族及其抑制剂在临床肿瘤治疗中的应用

人类表皮生长因子受体(human epidermal growth factor receptor,HER)家族属于酪氨酸激酶(tyrosine kinases,TK)的跨膜蛋白受体,包括4个成员,分别是HER1(EGFR)、HER2(ErbB2)、HER3(ErbB3)、HER4(ErbB4),能调节细胞生长、分化、迁移及其他细胞反应。     

靶向人表皮生长因子受体3单克隆抗体抗肿瘤的研究进展

人表皮生长因子受体（human epidermal growth factor receptor,HER/ ErbB）3是表皮生长因子受体家族成员之一。大量基础研究和临床试验表明,ErbB3在整个表皮生长因子受体信号传导通路以及肿瘤耐药性作用中发挥着至关重要的作用。此文综合近年来国内外对靶向ErbB3单克隆抗体（单抗）抗肿瘤的研究进展,对ErbB3参与肿瘤进程的机制、靶向ErbB3单抗对肿瘤的抑制作用,以及靶向ErbB3单抗抗肿瘤的作用机制进行综述。     

神经调节因子Neuregulin-1及其受体ErbB2、ErbB4在恒河猴大脑、小脑的表达及分布

目的神经调节因子（Neuregulin-1,Nrgl）是类表皮样生长因子家族重要成员,本研究观察比较恒河猴大脑皮质、白质及小脑皮、白质Nrgl及其受体ErbB2、ErbB4表达及分布。方法使用苏木精-伊红（HE）染色观察恒河猴大脑及小脑皮质、白质基本结构形态。使用免疫荧光双标法检测恒河猴大脑及小脑皮质、白质中Nrgl及其受体ErbB2和ErbB4表达与分布。结果免疫荧光显示Nrgl可与其受体ErbB2或ErbB4共定位表达于恒河猴大脑皮质部分细胞中;而在大脑白质,仅Nrgl与ErbB4存在明显定位。在小脑皮质细胞以及白质中均可见Nrgl与ErbB2明显定位,而ErbB4荧光信号则不明显,且Nrgl与ErbB4无明显共定位。结论本研究提示Nrgl及其受体ErbB2、ErbB4在恒河猴大脑小脑皮质及白质中存在着差异性表达和共定位．以Nrgl／ErbB为基础的旁分泌或自分泌机制有可能参与高等动物脑功能活动。     

肿瘤分子靶向治疗的研究进展

近年来，随着分子生物学技术的提高和对肿瘤发病机制从细胞、分子水平的进一步认识，分子靶向治疗已成为肿瘤医学的发展方向。其中以受体酪氨酸激酶为治疗靶点的分子靶向治疗受到国内外肿瘤界的普遍关注。它的ErbB受体家族通过基因扩增、过度表达和突变导致信号传导的增加与很多肿瘤及其不良预后呈正相关。     

PTEN基因与肿瘤耐药

肿瘤对抗肿瘤药物产生耐受性是肿瘤内科治疗失败的主要原因.PTEN是一种具有双特异性磷酸酶活性的抑瘤基因,其失活与多种肿瘤的发生发展密切相关.近年来的研究表明,PTEN在肿瘤耐药中发挥着重要作用.PTEN失活可介导肿瘤对表皮生长因子受体(EGFR)酪氨酸激酶抑制剂、抗Her-2/ErbB2人源化单克隆抗体曲妥珠单抗(trastuzumab)、抗EGFR人/鼠嵌合型单克隆抗体西妥昔单抗(cetuximab)、NOTCH1抑制剂、顺铂、阿霉素和紫杉醇等的耐受性,其机制与PTEN对PI3K-AKT信号途径的抑制有关.现综述PTEN基因的生物学特性及其在近年研究较多的几种肿瘤靶向药物耐药中的作用特征.     

HER-2和CDK4在非小细胞肺癌中的表达及临床意义

Her-2/neu(Human eptdermal growth Factor receptor-2)是一个编码跨膜酪氨酸激酶的EGFR家族的一个原癌基因,是表皮生长因子受体家族中成员,参与一系列复杂的细胞信号传导,调节肿瘤增殖、细胞凋亡、黏附迁移和血管发生、药物抵抗等,在肿瘤发生发展中起重要作用.     

The potential role of the EGFR/ERBB2 heterodimer in breast cancer

Epidermal growth factor receptor (EGFR) and ErbB2 are the best-characterised members of the ErbB family of receptor tyrosine kinases. Both receptors are frequently deregulated in human cancers and both are targets for anticancer drugs. ErbB2 amplification and overexpression are associated with a poor prognosis in breast cancer patients. Over the last decade, evidence has revealed that ErbB2 interacts with EGFR in order to achieve its full oncogenic potential. Therefore, assessment of EGFR and ErbB2 coexpression can potentially predict the outcome of the disease as well as success of therapies better than the assessment of single receptors. Moreover, it is not single-agent therapies, targeting one receptor, but combinations or several receptor-targeted therapies that may be the best way to fight cancer.     

Targeting ErbB receptors in high-grade glioma

High-grade gliomas, including glioblastoma, are among the most malignant and treatment-refractory human neoplasms. The tumors show high levels of resistance to conventional therapies (i.e. surgery, irradiation, and chemotherapy), and despite treatment advances patient outcome remains poor. New therapeutic options are needed. An especially interesting idea is the rational development of new therapies targeting molecules in cancer specific signaling pathways, thereby ideally increasing treatment efficacy and minimizing toxicity. Clearly, rational design requires thorough understanding of the molecular pathogenesis and resistance mechanisms. One highly promising approach is the targeted inhibition of ErbB growth factor receptors, which are recognized as key signaling pathways in many types of human tumors, including high-grade glioma. The ErbB receptor family of tyrosine kinases comprises four members: epidermal growth factor receptor (EGFR/ErbB1/HER1), ErbB2 (HER2/neu), ErbB3 (HER3) and ErbB4 (HER4). Physiologically, signaling is induced by ligand initiated receptor homo- or heterodimerization, activating intracellular downstream signaling pathways and leading to increased cell proliferation, anti-apoptosis and migration. A truncated, constitutively activated mutant EGFR (EGFRvIII) is associated with poor survival in GBM. Thus, to date anti-ErbB approaches are mainly focused on EGFR. The two major classes of anti-ErbB therapeutics are monoclonal antibodies (e.g. cetuximab, panitumumab) and small molecule Tyrosine kinase inhibitors (TKI, e.g. gefitinib, erlotinib, lapatinib). Some compounds entered clinical trials already, but clinical efficacy needs to be enhanced. Here we review current therapeutic advances targeting ErbB receptors in high-grade gliomas, and give a concise overview on current understanding of ErbB biology in gliomas, paving the way to novel rational therapeutic development.     

Targeting the EGFR-family for therapy: biological challenges and clinical perspective

Members of epidermal growth factor receptor (EGFR) or ErbB receptor family play a critical role in a wide range of human cancers. In the past decade, there has been a remarkable progress in developing ErbB targeted therapeutics. However, a substantial portion of patients has non-responsive disease or subsequently shows evidence of tumour relapse following initial success with anti-ErbB agents. Improved insights into the biology of ErbB receptor family have led to more effective second- and third-generation anti-ErbB therapies. In this review, we have summarised salient features of the ErbB receptor physiology and highlighted key mechanisms involved in abnormal ErbB signalling in tumorigenesis. The rationale of anti-ErbB receptor therapies are outlined along with key mechanisms proposed for resistance to treatment as well as the current concept of combined anti-ErbB therapies. In conclusion, improved understanding of the molecular pathways that confer resistance to anti-ErbB therapeutics will be essential in minimising tumour resistance to ErbB targeted treatments.     

Cellular and in vivo activity of JNJ-28871063, a nonquinazoline pan-ErbB kinase inhibitor that crosses the blood-brain barrier and displays efficacy against intracranial tumors

JNJ-28871063 is a potent and highly selective pan-ErbB kinase inhibitor from a novel aminopyrimidine oxime structural class that blocks the proliferation of epidermal growth factor receptor (EGFR; ErbB1)- and ErbB2-overexpressing cells but does not affect the growth of non-ErbB-overexpressing cells. Treatment of human cancer cells with JNJ-28871063 inhibited phosphorylation of functionally important tyrosine residues in both EGFR and ErbB2 and blocked downstream signal transduction pathways responsible for proliferation and survival. A single dose of compound reduced phosphorylation of ErbB2 receptors in tumor-bearing mice, demonstrating target suppression in vivo. Tissue distribution studies show that JNJ-28871063 crosses the blood-brain barrier and penetrates into tumors, where it is able to accumulate to higher levels than those found in the plasma. JNJ-28871063 showed oral antitumor activity in human tumor xenograft models that overexpress EGFR and ErbB2. In an intracranial ErbB2-overexpressing tumor model, JNJ-28871063 extended survival relative to untreated animals. The brain is a primary site of metastasis for EGFR-overexpressing lung cancers and ErbB2-overexpressing breast cancers. Therefore, the ability to penetrate into the brain could be an advantage over existing therapies such as trastuzumab (Herceptin) and cetuximab (Erbitux), which are antibodies and do not cross the blood-brain barrier. These results show that JNJ-28871063 is orally bioavailable, has activity against EGFR and ErbB2-dependent tumor xenografts, and can penetrate into the brain and inhibit ErbB2-overexpressing tumor growth.     

Desensitization by Different Strategies of Epidermal Growth Factor Receptor and ErbB4

Four transmembrane tyrosine kinases constitute the ErbB protein family: epidermal growth factor receptor (EGFR) or ErbB1, ErbB2, ErbB3, and ErbB4. In general, the structure and mechanism of the activation of these members are similar. However, significant differences in homologous desensitization are known between EGFR and ErbB4. Desensitization of ligand-occupied EGFR occurs by endocytosis, while that of ErbB4 occurs by selective cleavage at the cell surface. Because ErbB4 is abundantly expressed in neurons from fetal to adult brains, elucidation of the desensitization mechanism is important to understand neuronal development and synaptic functions. Recently, it has become clear that heterologous desensitization of EGFR and ErbB4 are induced by endocytosis and cleavage, respectively, similar to homologous desensitization. It has been reported that heterologous desensitization of EGFR is induced by serine phosphorylation of EGFR via the p38 mitogen-activated protein kinase (p38 MAP kinase) pathway in various cell lines, including alveolar epithelial cells. In contrast, the protein kinase C pathway is involved in ErbB4 cleavage. In this review, we will describe recent advances in the desensitization mechanisms of EGFR and ErbB4, mainly in alveolar epithelial cells and hypothalamic neurons, respectively.     

The epidermal growth factor receptor gene family as a target for therapeutic intervention in numerous cancers: what's genetics got to do with it?

Over the past 30 years, a relatively simple growth factor and its cognate receptor have provided seminal insights into the understanding of the genetic basis of cancer, as well as growth factor signalling. The epidermal growth factor (EGF), its cognate receptor (EGFR) and related family members have been shown to be important in normal, as well as the malignant growth of many cell types including: glioblastomata, astrocytomas, medulloblastomata, non-small cell lung carcinoma (NSCLC) and breast cancer. This review summarises the history of the EGFR gene and the v-ErbB oncogene, as well as diverse approaches developed to inhibit EGFR activity. The two most advanced therapies use either small-molecule cell membrane permeable kinase inhibitors or antibodies which prevent receptor activation. Recent clinical trials indicate that certain NSCLC patients have mutations in the EGFR gene which makes them more responsive to kinase inhibitors. These mutations appear to enhance the ability of the ligand to activate EGFR activity and also prolong the binding of the EGFR inhibitor to the kinase domain. Evidence to date suggests that these EGFR mutations in NSCLC occur more frequently in Japan than in the western hemisphere. Although these mutations are correlated with enhanced efficacy to the inhibitors in NSCLC, they can not explain or predict the sensitivity of many other cancer patients to the beneficial effects of the EGFR kinase inhibitors or antibody mediated therapy. As with as other small-molecule kinase inhibitors and susceptible diseases (e.g., imatinib and chronic myeloid leukaemia), resistance to EGFR inhibitors has been reported recently, documenting the requirement for development of multi-pronged therapeutic approaches. EGFR kinase inhibitors are also being evaluated as adjuvants in hormonal therapy of breast cancer - especially those which overexpress EGFR. Genetically engineered antibodies specific for the EGFR family member ErbB2 have been developed which show efficacy in the treatment of primary, and prevent the relapse of, breast cancer. Clearly, the EGF/EGFR signalling cascade has, and continues to play, an important role in the development of novel anticancer targeted therapies.     

Novel substituted quinazolines for potent EGFR tyrosine kinase inhibitors

The type I receptor tyrosine kinases (RTKs) are involved in various aspects of cell growth, survival, and differentiation. Among the known RTKs, the epidermal growth factor receptor (EGFR) and ErbB-2 (HER-2) are two widely studied proteins that are prototypic members of the ErbB family which also includes ErbB-3 (Her-3) and ErbB-4 (Her-4). Overexpression of ErbB-2 and EGFR has been associated with aggressive disease and poor patient prognosis in a range of human tumour types (e.g. breast, lung, ovarian, prostate, and squamous carcinoma of head and neck). Disruption of signal transduction of these kinases has been shown to have an antiproliferative effect. Various approaches have been developed to target the ErbB signalling pathways including monoclonal antibodies (trastuzumab/Herceptin? and cetuximab/Erbitux?) directed against the receptor, and synthetic tyrosine kinase inhibitors (gefitinib/Iressa? and erlotinib/Tarceva?). Since many tumours overexpress ErbB receptors, simultaneous targeting of multiple ErbB receptors therefore becomes a promising approach to cancer treatment. Lapatinib (Tykerb?), a potent dual EGFR/ErbB-2 inhibitor, was approved for the treatment of ErbB-2-positive breast cancer. Despite years of intensive research on EGFR inhibitors, there is a surprising dearth of chemically distinct small inhibitors with a high degree of selectivity. There is also a need for new scaffolds due to the recent finding of EGFR mutations which render the kinase resistant to gefinitib and erlotinib. The structures under study will be quinazolines with different substituents. The structure-activity relationships and biological evaluation of compounds published during the last four years will be reviewed herein.     

The dual targeting of EGFR and ErbB2 with the inhibitor Lapatinib corrects high glucose-induced apoptosis and vascular dysfunction by opposing multiple diabetes-induced signaling changes

The epidermal growth factor receptors, EGFR and EGFR2 (ErbB2), appear important mediators of diabetes-induced vascular dysfunction. We investigated whether targeted dual inhibition of EGFR and ErbB2 with Lapatinib would be effective in treating diabetes-induced vascular dysfunction in a rat model of type 1 diabetes. In streptozotocin-induced diabetes, chronic 4-week oral or acute, ex vivo, administration of Lapatinib prevented the development of vascular dysfunction as indicated by the attenuation of the hyper-reactivity of the diabetic mesenteric vascular bed (MVB) to norephinephrine without correcting hyperglycemia. Chronic in vivo or acute ex vivo Lapatinib treatment also significantly attenuated diabetes-induced increases in phosphorylation of EGFR, ErbB2, ERK1/2, AKT, ROCK2 and IkB-alpha as well as normalized the reduced levels of phosphorylated FOXO3A, and eNOS (Ser1177) in the diabetic MVB. Similar results were observed in vascular smooth muscle cells (VSMCs) cultured in high glucose (25?mM) treated with Lapatinib or small interfering RNA (siRNA) targeting the ErbB2 receptor. Lapatinib also prevented high glucose-induced apoptosis in VSMC. Thus, Lapatinib corrects hyperglycemia-induced apoptosis and vascular dysfunction with concomitant reversal of diabetes or high glucose-induced signaling changes in EGFR/ErbB2 and downstream signaling pathways implying that targeted dual inhibition of EGFR/ErbB2 might be an effective vasculoprotective treatment strategy in diabetic patients.     

The epidermal growth factor receptor gene family as a target for therapeutic intervention in numerous cancers: what’s genetics got to do with it?

Over the past 30 years, a relatively simple growth factor and its cognate receptor have provided seminal insights into the understanding of the genetic basis of cancer, as well as growth factor signalling. The epidermal growth factor (EGF), its cognate receptor (EGFR) and related family members have been shown to be important in normal, as well as the malignant growth of many cell types including: glioblastomata, astrocytomas, medulloblastomata, non-small cell lung carcinoma (NSCLC) and breast cancer. This review summarises the history of the EGFR gene and the v-ErbB oncogene, as well as diverse approaches developed to inhibit EGFR activity. The two most advanced therapies use either small-molecule cell membrane permeable kinase inhibitors or antibodies which prevent receptor activation. Recent clinical trials indicate that certain NSCLC patients have mutations in the EGFR gene which makes them more responsive to kinase inhibitors. These mutations appear to enhance the ability of the ligand to activate EGFR activity and also prolong the binding of the EGFR inhibitor to the kinase domain. Evidence to date suggests that these EGFR mutations in NSCLC occur more frequently in Japan than in the western hemisphere. Although these mutations are correlated with enhanced efficacy to the inhibitors in NSCLC, they can not explain or predict the sensitivity of many other cancer patients to the beneficial effects of the EGFR kinase inhibitors or antibody mediated therapy. As with as other small-molecule kinase inhibitors and susceptible diseases (e.g., imatinib and chronic myeloid leukaemia), resistance to EGFR inhibitors has been reported recently, documenting the requirement for development of multi-pronged therapeutic approaches. EGFR kinase inhibitors are also being evaluated as adjuvants in hormonal therapy of breast cancer – especially those which overexpress EGFR. Genetically engineered antibodies specific for the EGFR family member ErbB2 have been developed which show efficacy in the treatment of primary, and prevent the relapse of, breast cancer. Clearly, the EGF/EGFR signalling cascade has, and continues to play, an important role in the development of novel anticancer targeted therapies.