表皮生长因子受体通路阻断在胰腺癌治疗中的进展

胰腺癌在全球肿瘤发病率中位居第13位,死亡率居第8位[1]。2011年我国新确诊胰腺癌80 344例,在我国肿瘤发病率中位居第10位,死亡72 723例,位居肿瘤所致死亡原因的第6位[2]。手术切除是治愈胰腺癌的唯一有效手段。然而,由于胰腺癌在发病早期缺乏特异性症状,多数患者确诊时已是局部进展期或发生远处转移而无法手术,能接受手术治疗者仅占15%~20%[3]。化学治疗(化疗)可改善晚期胰腺     

表皮生长因子受体抑制剂与肺纤维化

酪氨酸蛋白激酶(tyrosine protein kinase，TPK)是一类能催化蛋白质酪氨酸磷酸化的蛋白激酶，其活性最早是在癌基因src产物上发现的。该酶能催化ATP的γ磷酸基转移到自身或底物的酪氨酸残基上，使酚羟基磷酸化，通过蛋白质磷酸化的级联反应传递信息，导致生物效应。酪氨酸蛋白激酶介导的细胞内信号传导TPK为一个大的结构多样的酶家族，分为受体型和非受体型两种。受体型TPK(receptor tyrosine kinase，RTK)是细胞内段具有酪氨酸激酶活性的一类跨膜受体，如血小板衍生生长因子受体(PDGFR)、成纤维细胞生长因子受体(FGFR)、表皮细胞生长因子受体(EGFR)等，非受体型TPK是细胞浆中具有酪氨酸激酶活性的蛋白质。     

表皮生长因子受体与胰腺癌的关系及以其为靶向治疗的研究进展

表皮生长因子受体（epidermal growth factor receptor，EGFR）是一种糖蛋白．具有酪氨酸蛋白激酶的活性，对表皮生长因子（epidermal growth factor，EGF）或转化生长因子（TGF）-α具有高度的亲和性．两者特异性结合后能激活一系列与细胞生长、增殖、转化有关的生化过程，并可参与肿瘤的发生和生长。而EGFR在胰腺癌中的表达明显高于正常胰腺组织，并且可能与胰腺癌的增殖、侵袭关系密切。近年来针对EGFR的信号转导系统．设计和合成特异性的EGFR抑制物，可望对胰腺癌的防治开辟新的途径。本文就EGFR与胰腺癌的关系以及以EGFR为靶向治疗胰腺癌方面的新进展作一综述。     

表皮生长因子受体抑制剂靶治疗癌症的新进展

分子靶向治疗从基础研究进入临床试验,新的分子靶点不断被发现,其中表皮生长因子受体(EGFR)以其在癌症发生、发展中的重要作用备受关注。本文就目前抗EGFR药物的作用机制、临床疗效和副作用的研究进展进行综述。     

表皮生长因子受体抑制剂及其突变在肺癌治疗中的研究进展

表皮生长因子受体及其抑制剂是肺癌分子靶向治疗的研究热点,表皮生长因子受体抑制剂已广泛运用于非小细胞肺癌治疗,近年发现表皮生长因子受体突变与其抑制剂的临床疗效关系密切.现就表皮生长因子受体抑制剂及其突变在肺癌治疗中的研究进展作一综述.     

表皮生长因子受体相关蛋白在肿瘤靶向治疗中的应用前景

靶向治疗是一种比较新的治疗方法,特别是干预表皮生长因子受体(epidermal growth factor receptor,EGFR)家族成员,可以有效抑制肿瘤的生长,但目前应用的靶向治疗药物,只能作用于EGFR或HER-2,不能同时作用于二者,并且肿瘤多表达不同水平的EGFR及不同的EGFR家族成员,而表皮生长因子受体相关蛋白是EGFR及其家族成员的共同的抑制剂,有望成为有效的靶向治疗药物.     

胰腺癌微血管的生成机制及其抑制剂的作用

肿瘤微血管生成在胰腺癌的发生转移过程中起重要作用，血管内皮生长因子、表皮生长因子、碱性纤雏母细胞生长因子等血管生长因子和基质金属蛋白酶反映肿瘤微血管的生长，肿瘤微血管的检测和抗血管生成治疗将为胰腺癌的诊断和治疗提供新的手段。     

表皮生长因子受体家族在结直肠肿瘤发生中的作用探讨

大肠癌是临床上最常见的恶性肿瘤之一，而大肠腺瘤则是大肠癌最重要的癌前病变。近年来国内外研究表明，癌基因编码的蛋白产物在信号传导过程中的不同环节发挥作用。表皮生长因子受体(Epidermal Growth Factor Receptor，EGFR)、c—erbB-2和c—erbB-3同属生长因子受体家族，在结构和功能上均相似，这些受体和生长因子结合后可启动细胞生长周期。     

EGFR抑制剂在胃癌中的研究进展

胃癌是常见的消化系恶性肿瘤,传统的化疗和放疗效果均不甚理想.表皮生长因子受体(epidermal growth factor receptor,EGFR)信号转导通路在胃癌细胞的增殖、血管生成、侵袭、转移等方面有重要作用.因此,针对EGFR的靶向药物已陆续开发并将逐步应于胃癌治疗的临床实践.本文就EGFR抑制剂在胃癌中...     

The role of epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of advanced stage non-small cell lung cancer

The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) like erlotinib and gefitinib have been extensively studied. Multiple randomized trials have evaluated the role of EGFR TKIs in advanced stage non-small cell lung cancer (NSCLC) as a monotherapy in the first line, or subsequent lines of therapy, and in the first line in the maintenance setting or in combination with chemotherapy. Most of these trials showed positive results in particular for selected patients with specific clinical characteristic and somatic activating mutation of EGFR. A further understanding of the mechanism of primary and secondary resistance has led to the development of promising novel agents designed to overcome resistance to EGFR.     

Acquired resistance of non-small cell lung cancer to epidermal growth factor receptor tyrosine kinase inhibitors

Activation of epidermal growth factor receptor (EGFR) triggers anti-apoptotic signaling, proliferation, angiogenesis, invasion, metastasis, and drug resistance, which leads to development and progression of human epithelial cancers, including non-small cell lung cancer (NSCLC). Inhibition of EGFR by tyrosine kinase inhibitors such as gefitinib and erlotinib has provided a new hope for the cure of NSCLC patients. However, acquired resistance to gefitinib and erlotinib via EGFR-mutant NSCLC has occurred through various molecular mechanisms such as T790M secondary mutation, MET amplification, hepatocyte growth factor (HGF) overexpression, PTEN downregulation, epithelial-mesenchymal transition (EMT), and other mechanisms. This review will discuss the biology of receptor tyrosine kinase inhibition and focus on the molecular mechanisms of acquired resistance to tyrosine kinase inhibitors of EGFR-mutant NSCLC.     

Lapatinib,a dual inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2, potentiates the antitumor effects of cisplatin on esophageal carcinoma

Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) overexpression occurs in over 30% of esophageal carcinomas. Combination therapies of EGFR‐ and HER2‐targeting agents with cytotoxic agents are considered a potential therapeutic strategy for esophageal cancer. The antitumor effects of lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER2, cisplatin alone, and the combination of the two drugs on esophageal cancer cells were evaluated. The growth inhibition activity of lapatinib, cisplatin, and lapatinib plus cisplatin was measured by 3‐(4,5)‐dimethylthiahiazo(‐z‐y1)‐3,5‐di‐phenytetrazoliumromide (MTT) assays, and the combination index values were calculated. Additionally, cell cycle distribution and cell apoptosis treated with lapatinib or cisplatin alone and the combination of the two drugs were detected by flow cytometry analysis. The activation of EGFR and HER2 signaling pathways was monitored by Western blot analysis. These experimental data showed that the combination of lapatinib and cisplatin synergistically inhibited cell proliferation and exhibited an enhanced pro‐apoptotic effect on esophageal cancer cells. The underlying mechanisms of potentiated effects of combined treatment were associated with reduced phosphorylation of EGFR and HER2, and the downstream signaling molecules AKT and extracellular regulated protein kinases (ERK). Our findings indicated that the combination of lapatinib and cisplatin is one of the promising treatment strategies for esophageal carcinomas with EGFR and HER2 overexpression.     

Efficacy and safety profile of combining agents against epidermal growth factor receptor or vascular endothelium growth factor receptor with gemcitabine-based chemotherapy in patients with advanced pancreatic cancer: A meta-analysis

ObjectivesSeveral clinical trials have been published on gemcitabine-based chemotherapy with or without addition of agents against epidermal growth factor receptor (EGFR) or vascular endothelium growth factor receptor (VEGFR) in patients with advanced pancreatic cancer, however, with diverse results. The objective of this study was to perform a meta-analysis of the published trials.MethodsThe database of CENTRAL, MEDLINE and EMBASE were searched. Eligible studies were randomized clinical trials (RCTs) that evaluated the efficacy and safety profile of adding targeted agents against EGFR or VEGFR to gemcitabine-based chemotherapy in patients with advanced pancreatic cancer. The primary outcome was overall survival (OS) while secondary outcomes included progression free survival (PFS) and overall response rate (ORR). Toxicity profiles were also assessed. Review Manager 5.1 was used to perform the analysis.ResultsResults reported from 6 RCTs involving 2733 patients were included in the analysis. Compared to gemcitabine-based chemotherapy alone, addition of an agent against EGFR resulted in significant longer OS [Hazard ratios (HR) 0.89 (0.79–0.99), p = 0.04] and longer PFS [HR 0.87 (0.79–0.97), p = 0.01], but no significant difference in ORR [RR 1.18 (0.82–1.70), p = 0.36]. The addition of an agent against VEGFR resulted in higher ORR [RR 1.54 (1.03–2.30), p = 0.04], but no advantage in OS [HR 0.95 (0.83–1.09), p = 0.47] or PFS [HR 0.97 (0.77–1.23), p = 0.82].ConclusionsAddition of an agent against EGFR to gemcitabine-based chemotherapy improved OS compared to gemcitabine-based chemotherapy alone in patients with advanced pancreatic cancer, while addition of an agent against VEGFR showed a modest improvement in ORR but not PFS and OS.     

The role of epidermal growth factor receptor in prognosis and treatment of gastric cancer

Despite tremendous efforts to reduce deaths due to gastric cancer, it represents the second leading cause of cancer-related deaths worldwide. EGF receptor (EGFR) plays important roles in gastric carcinogenesis by regulation of cell cycle, angiogenesis and apoptosis. This review evaluates the functions, mechanisms and clinical uses of EGFR in gastric cancer. Although EGFR targeted single therapy shows limited effect, the combination of EGFR targeted agents with traditional chemotherapy regimens may bring about important progress in cancer therapy. More clinical trials should be performed to clarify both the prognostic and therapeutic value of EGFR in gastric cancer.     

表皮生长因子受体酪氨酸激酶抑制剂与化疗联合应用治疗非小细胞肺癌的研究进展

吉非替尼联合化疗的Ⅲ期临床试验INTACT1和INTACT2的结果表明,与单纯化疗相比,吉非替尼与健择+顺铂或紫衫醇+卡铂联合,不能提高非小细胞肺癌治疗的有效率和生存率.对于这一阴性结果,部分学者认为是由于缺乏对敏感人群的选择以及化疗药与表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor tyrasine kinase inhibitors,EGFR-TKI)同时使用可能存在相互拮抗作用.基础实验及临床试验表明,化疗后序贯给予EGFR-TKI维持或化疗间期间断给予EGFR-TKI的联合治疗方式,有较好的临床应用前景.     

The role of ramucirumab with docetaxel in epidermal growth factor receptor mutant and wild-type non-small cell lung cancer

BackgroundRamucirumab paired with docetaxel extends progression free survival and overall survival in non-small cell lung cancer (NSCLC) following progression on platinum therapy. There is some data that epidermal growth factor receptor (EGFR) mutant disease would respond better to vascular endothelial growth factor receptor (VEGFR) therapy than EGFR wild type disease.MethodsThis retrospective, single-institution cohort study reports outcomes of patients who received docetaxel with or without ramucirumab according to EGFR status. Clinical data including age, performance status, metastatic burden and prior treatment history was obtained and reported with time on treatment and overall survival as primary endpoints. Data analysis was performed for three cohorts: EGFR mutant disease receiving docetaxel and ramucirumab (EGFR-doce/ram), EGFR mutant disease receiving docetaxel alone (EGFR-doce) and EGFR wild type disease receiving docetaxel and ramucirumab (WT-doce/ram).ResultsPatients in the EGFR-doce/ram cohort had a median time on docetaxel of 1.4 months (95% CI: 0.72–5.2 months) and of 0.8 months (95% CI: 0.2–6.5 months) on ramucirumab. Patients in the EGFR-doce cohort were on docetaxel for a median 1.4 months (95% CI: 0.9–2.4 months). Patients in the WT-doce/ram cohort had a median time on docetaxel of 2.3 months (95% CI: 1.6–4.1 months) and on ramucirumab of 1.4 months (95% CI: 0.8–3.2 months). There was no significant difference between time on ramucirumab or docetaxel between the cohorts. Overall survival for the three cohorts was noted to be 6.7 months (95% CI: 2.5–16.2 months) for the EGFR-doce/ram cohort, 4.9 months (95% CI: 4.2–12.5 months) for the EGFR-doce cohort and 6.6 months (95% CI: 4.3–12.8 months) for the WT-doce/ram cohort. There was no significant difference in overall survival between the cohorts.ConclusionsOur data did not support the initial hypothesis that patients with EGFR mutant disease would do better with the addition of ramucirumab. Our study was limited by small sample size, retrospective nature and inability to control for confounders including prior bevacizumab or immune checkpoint inhibitor (ICI) exposure. This study offers real-world estimates to clinicians and patients about the length of time they can expect to derive benefit from the combination of ramucirumab and docetaxel.     

Expression of transforming growth factor alpha and epidermal growth factor receptor in human hepatocellular carcinoma

Abstract: Transforming growth factor alpha (TGF-alpha) is thought to be involved in liver regeneration, cellular proliferation, and hepatocarcinog-enesis. We have looked at the relationship between TGF-alpha and it's receptor, and have attempted to relate the expression of TGF-alpha and it's receptor to the differentiation of hepatocellular carcinoma (HCC) on serial sections of HCC. We examined immunohistochemically the expression of the TGF-alpha and of epidermal growth factor receptor (EGFR) proteins in the same area of 53 nodules (<5 cm in diameter) of HCC obtained from patients. Immnnoreactive proteins were visualized by using a biotin-streptoavidin system (LSAB Kit, Dako). TGF-alpha was strongly expressed in 29 of 53 (54.7%) nodules. Specimens strongly positive for TGF-alpha were found mainly in well-differentiated HCC, while specimens positive for EGFR were found mainly in poorly differentiated HCC (p<0.05). In the tissues that stained weakly positive for TGF-alpha, the expression of EGFR differed significantly, according to the degree of HCC histologic differentiation (p<0.05). These results led us to speculate that the expression of TGF-alpha and EGFR might be related to the pattern of histologic differentiation of HCC.     

Potential role of the epidermal growth factor receptor in human pancreatic cancer

The epidermal growth factor (EGF) receptor is a transmembrane protein that has tyrosine kinase activity. It is activated by both EGF and transforming growth factor-alpha (TGF-alpha). Human pancreatic cancer cells overexpress the EGF receptor and exhibit a parallel increase in EGF receptor mRNA without a detectable increase in the number of gene copies coding for the receptor. These cells also produce TGF-alpha and are capable of binding exogenous TGF-alpha. They often recycle EGF, but markedly and rapidly degrade TGF-alpha. However, TGF-alpha is 10-100-fold more potent than EGF in enhancing their anchorage-independent growth. Both growth factors induce EGF receptor down-regulation, but EGF is more efficient than TGF-alpha in this regard. The concomitant overexpression of the EGF receptor and production of TGF-alpha, the recycling of EGF, and the attenuated ability of TGF-alpha to down-regulate the EGF receptor may combine to provide a distinct growth advantage to human pancreatic cancer cells.