Tyrphostins AG1478对内分泌耐药乳腺癌细胞的作用

目的：研究表皮生长因子受体（EGFR）抑制剂对内分泌治疗耐药的激素依赖性乳腺癌细胞的作用,探讨EGFR抑制剂的应用前景.方法：选择雌激素受体（ER）阳性的乳腺癌细胞MCF-7,建立三苯氧胺（TAM）耐药的乳腺癌细胞（T-MCF-7）.研究EGFR抑制剂Tyrphostins AG1478对T-MCF-7细胞的作用,采用四甲基偶氮唑蓝（MTT）比色法进行细胞生长抑制试验,流式细胞仪（FCM）检测细胞周期的影响,Western blot方法分析EGFR及其信号通路的改变.结果：MCF-7细胞在持续给予TAM（10-7mol/L）处理6个月后获得耐药细胞T-MCF-7.与MCF-7细胞相比,T-MCF-7对AG1478的敏感性增高.AG1478可使T-MCF-7细胞周期阻滞,增殖指数下降,凋亡率增加;对T-MCF-7细胞的EGFR和细胞外信号调节激酶（ERK1/2）蛋白水平无影响,但使其磷酸化-ERK1/2水平下降,降低了EGFR下游信号通路的活性水平.结论：激素依赖性乳腺癌细胞给予TAM长期处理后,更依赖于EGFR信号转导通路的作用.EGFR抑制剂可抑制EGFR信号通路的活性,提高乳腺癌内分泌治疗的效果.     

肝细胞生长因子受体/表皮生长因子受体交互作用与肿瘤耐药

肝细胞生长因子受体(mesenchymal-epithelial transition factor, MET)通路在肿瘤发生过程中具有重要作用,包括促进细胞增殖、抑制细胞凋亡、促进肿瘤血管生成、促进肿瘤细胞迁移及侵袭、转移等多个过程,涉及质膜、胞内共作用因子及下游效应蛋白的协同作用.体内、外实验证实,MET与表皮生长因子受体(epithelial growth factor receptor, EGFR)之间存在复杂的交互作用,两者共同参与细胞增殖、细胞运动及下游信号通路活化等多种细胞生物学事件,其中一些与肿瘤发生、进展密切相关.MET有可能通过"置换"EGFR活性而参与EGFR抑制剂的耐药发生.文中综述了肝细胞生长因子(hepatocyte growth factor,HGF)-MET和EGFR通路在肿瘤发生、发展过程中的重要作用,讨论了两者交互作用引起EGFR抑制剂耐药的可能机制,在此基础上提出联合使用EGFR和MET靶向抑制剂在克服EGFR抑制剂获得性耐药方面的应用前景.     

表皮生长因子受体抑制剂耐药机制的研究进展

表皮生长因子受体(EGFR)是抗肿瘤治疗中重要的分子靶点,两类抗表皮生长因子受体(anti-EGFR)药物:单克隆抗体及小分子酪氨酸激酶抑制剂已成功应用于临床,但其原发和继发耐药问题也日益受到关注。肿瘤对anti-EGFR药物耐药的可能机制包括:EGFR、K-ras、Braf突变;配体的自分泌或旁分泌;原癌基因MET扩增;下游通路持续活化;激活替代通路;肿瘤诱导不依赖于EGFR活化的血管生成等。     

表皮生长因子受体信号通路与胰腺癌的靶向治疗

表皮生长因子受体(EGFR)信号通路在胰腺癌的增殖、转移、血管形成等方面有重要作用,人们对胰腺癌的EGFR信号通路进行了深入全面的研究,并对EGFR抑制剂和K-ras抑制剂治疗胰腺癌进行了大量临床试验。虽然厄洛替尼被美国食品药物管理局批准用于治疗晚期胰腺癌,但其仅延长中位生存期不到10 d,且皮疹、腹泻等不良反应影响了患者生活质量,是否真正使患者临床受益仍存在争议。     

EGFR突变的非小细胞肺癌耐药机制及其克服新策略

表皮生长因子受体(EGVR)突变的非小细胞肺癌(NSCLC)被列为一个与临床相关的、独特的肺癌亚群.虽然EGFR突变的肿瘤患者增加了对酪氨酸激酶抑制剂(TKI)的敏感性,但其耐药仍然是一个主要的临床问题.针对原发和获得性耐药不同的分子机制,包括应用第2代或第3代TKI,以及与EGFR下游信号通路抑制剂的组合用药等多项临...     

转移性结直肠癌靶向药物的耐药机制及中医药治疗策略

分子靶向治疗是转移性结直肠癌（mCRC）的主要治疗方法之一,联合化学疗法可使患者的总生存期（OS）、无进展生存期（PFS）显著获益。临床常用的分子靶向药物主要包括小分子信号传导抑制剂和大分子单克隆抗体。但靶向治疗后期产生的耐药问题成为临床上治疗的关键难题。研究表明,靶向药物耐药机制可能与多种因素相关,包括表皮生长因子受体（EGFR）、血管内皮生长因子（VEGF）、人表皮生长因子受体-2(HER2)等相关细胞信号通路异常以及肿瘤微环境改变等。近年来,研究发现中医药治疗在逆转靶向药物耐药方面颇有成效。因此,该文对CRC分子靶向治疗耐药机制以及中医药应对策略进行论述,并对逆转靶向耐药的中药及其有效成分进行探讨。     

EGFR抑制剂耐药机制的研究进展及治疗策略

EGFR是调节细胞内环境稳态的一种酪氨酸激酶,其与配体结合后可影响细胞增殖、凋亡、迁移、存活、血管生成和肿瘤发生等一系列复杂过程,EGFR抑制剂已逐渐应用于临床肿瘤治疗。但随着时间的推移,EGFR抑制剂靶向治疗出现了耐药现象。本文将对EGFR抑制剂的研究现状及耐药机制做一简短的概述,冀希为优化、整合EGFR靶向治疗提供参考。     

转移性结直肠癌抗EGFR治疗耐药机制的研究进展

表皮生长因子受体(epidermal growth factor receptor,EGFR)是转移性结直肠癌(metastatic colorectal cancer, mCRC)的主要治疗靶点之一,然而抗EGFR治疗的耐药一直是亟待解决的临床难题。肿瘤细胞本身EGFR相关信号通路异常激活,基因组不稳定性等遗传学或表观遗传学改变是引发耐药最常见的机制,近期也有研究发现肿瘤微环境中细胞丰度和细胞因子的变化等也是引发抗EGFR治疗耐药的重要机制。我们将从肿瘤细胞和肿瘤微环境两个方面,对mCRC抗EGFR治疗的耐药机制进行综述。     

整合素与EGFR交叉信号通路在恶性肿瘤侵袭转移机制中的研究进展

侵袭转移是恶性肿瘤的基本生物学特征,是临床抗肿瘤失败及患者死亡的最主要原因。整合素（integrin）作为黏附分子家族的成员之一,通过介导细胞与细胞或细胞与基质间的黏附作用,经一系列信号转导,在肿瘤转移进程中发挥关键作用,且与肿瘤耐药机制有很大相关性。而表皮生长因子受体（epidermal growth factor receptor,EGFR）在恶性肿瘤转移及耐药中亦扮演着重要角色。随着研究深入,整合素家族与EGFR信号通路的交叉关系逐步明确,这将进一步揭开肿瘤转移的面纱,为以后新药开发、临床应用开辟新的思路。现就整合素家族中部分成员分子与EGFR信号通路间存在的交叉关系及其在肿瘤转移中的作用做简要概述。     

鼻咽癌中EGFR调控APP信号通路的初步研究及其意义

目的 探索鼻咽癌(nasopharyngeal carcinoma,NPC)中表皮生长因子受体(epidermal growth factor receptor,EGFR)调控β淀粉样蛋白前体(amyloid beta A4 protein,APP)的信号通路及其临床意义.方法 采用转化生长因子(transforming growth factors-α,TGF-α)诱导CNE2细胞24 h作为研究模型,分别采用EGFR酪氨酸激酶的选择性小分子抑制剂PD153035,MAPK抑制剂PD98059,PI3K抑制剂Wortmannin处理2 h再用TGF-α作用24 h作为实验组,Western blot检测阻断剂APP蛋白的表达和分泌变化情况.免疫组化检测EGFR和APP蛋白在NPC与慢性鼻咽炎症上皮组织中的表达差异.结果 PD153035+TGF-α组APP蛋白表达与分泌有所下调,wortmannin+TGF-α组APP蛋白下调明显,PD98059+TGF-α组APP表达无明显变化.EGFR和APP在NPC组织中的表达高于鼻咽炎症上皮组织,且差异有统计学意义(P＜0.05).结论 NPC中APP蛋白主要受EGFR信号通路中的PI3K调控,EGFR和APP与NPC的发生有关.     

EGFR单抗的耐药机制及食管癌治疗进展

表皮生长因子受体(EGFR)在多种上皮性肿瘤中过表达,其异常活化与恶性肿瘤的发生、发展密切相关。分子靶向药物EGFR单抗已经成功应用于头颈部鳞癌、结直肠癌等;但其耐药问题严重制约着临床疗效。近年来对EGFR单抗在肿瘤中的耐药机制、疗效相关的分子标志物及解决耐药策略的研究凸显重要;同时已有临床研究显示EGFR单抗在食管癌中也取得较好的临床疗效。     

非小细胞肺癌分子靶向治疗的毒性反应研究进展

近年来,非小细胞肺癌的分子靶向治疗成为研究的热点,分子靶向治疗药物主要包括表皮生长因子受体 (epidermal growth factor receptor,EGFR)单克隆抗体、血管内皮生长因子受体(vascular endothelial growth factor receptor,VEGFR)单克隆抗体、表皮生长因子受体酪氨酸激酶抑制剂等。这些药物在临床上都取得了一定的疗效,同时也出现了皮疹、腹泻、高血压等若干毒性反应,还有一些新药,如索拉非尼、舒尼替尼、伏立诺他、范得它尼等,都有相关的毒性反应。分子靶向治疗毒性反应严重影响了患者的生活质量和服药的依从性。本文就非小细胞肺癌分子靶向药物的毒性反应及处理措施作一综述。     

Update of epidermal growth factor receptor-tyrosine kinase inhibitors in non-small-cell lung cancer

Lung cancer is the leading cause of cancer-related death in the world. Prior to the era of targeted therapy, platinum-based doublet chemotherapy was the first-line therapy of choice for patients with metastatic non-small-cell lung cancer (NSCLC). The availability of agents that target epidermal growth factor receptor (EGFR)-tyrosine kinase, as well as inhibitors against anaplastic lymphoma kinase (ALK) gene rearrangement or ROS-1 gene rearrangement product, has provided promising clinical benefits in specific subpopulations of NSCLC. At present, only first-generation EGFR-tyrosine kinase inhibitors (TKIs) (erlotinib and gefitinib) are available for clinical use. Second-generation irreversible EGFR-TKIs, such as afatinib, are still in clinical trials. In current clinical practice, EGFR-TKI is the first-line treatment of choice for metastatic NSCLC patients with tumor EGFR mutation or as salvage therapy in NSCLC patients who received systemic chemotherapy previously. Platinum-based doublet chemotherapy continues to be the standard of care for those treatment-naïve patients with EGFR wild -type tumor or unknown EGFR status. Even though all investigators agree with the use of EGFR-TKI as the first-line treatment in tumor EGFR-mutated patients, only 10–30% of NSCLC patients have mutated EGFR, and there was no obvious survival difference when EGFR-TKIs were used in a second-line setting versus a first-line treatment in EGFR-mutated patients. Thus, the molecular complexity of lung cancer emphasizes the need for optimizing treatment by seeking a more personalized approach to care, including searching for driver oncogenes, managing the emergence of resistance and overcoming that resistance, and optimizing the sequence of treatment. Numerous other novel targeted agents are now in clinical development, including new agents targeting novel pathways and those that may have the potential to overcome the limitations or resistance associated with currently available EGFR-TKIs. In this report, we review the clinical data of EGFR-TKIs as molecular-targeted therapies in NSCLC.     

Detecting the epidermal growth factor receptors status in non-small cell lung cancer

Non-small cell lung cancer is one of the leading causes of all cancer deaths, but despite years of research, it is still difficult to predict the response and clinical outcome of the disease. In recent years, new treatment strategies targeting the epidermal growth factor receptors (EGFR) have been developed. EGFR is one of the most frequently over expressed proteins in various cancers, including lung cancer, and signaling through this receptor has been known to cause tumor progression as well as resistance to different treatments. Therefore, EGFR has become an attractive target for various treatment strategies. However, it is important to note that not all patients with lung cancer are suitable for targeted treatment, and that patients should be selected for this treatment. Several studies have proven that the status of the EGFR can be both an indicator of suitability for treatment with, and predict the likelihood of response to EGFR targeted therapy. There are many standard techniques to be used for the detection of EGFR. This overview summarizes the ongoing and future investigations to determine the status of the EGFR.

     

表皮生长因子受体敏感突变肺癌靶向治疗原发耐药的机制及临床对策

针对伴有表皮生长因子受体（EGFR）敏感突变的非小细胞肺癌,基于小分子抑制剂的靶向治疗在临床上取得了极大成效,但仍面临着原发耐药/不敏感的问题。初始治疗的有效比例及疗效深度决定了患者的远期生存。本文梳理了关于原发耐药的主要机制,包括突变亚型结构、原发T790M、合并突变、免疫状态等的影响及其相互关系,以及目前有效药物的证据,提出了多基因分型、精准靶向、“鸡尾酒”疗法等克服原发耐药的管理策略,并展望了该领域的发展趋势,为同行们的临床实践及科研方向提供思路。     

A CLONALLY DERIVED CELL LINE, 9L－EGFR IS USEFUL FOR THE STUDIES OF CANCER CELLS BEARING EGF RECEPTOR

Since the epidermal growth factor receptor (EGFR) is a key regulator in ceU sig-naling pathways of cancer ceU. To investigate the mechanism between cancer cells survival and its EGFR expression, drug selection of cancer cells target therapy, we generated a cell line, 9L-EGFR, which stably expressed human EGFR; the parental rat glioma cell line, 9L, does not con-tain endogenous EGFR message or protein. Our results show that 9L- EGFR cells had high levels of EGFR on their cell surface by using RT- PCR, Western analysis and Flow cytometry analysis.The EGFR transfected into 9L cells was capable of being activated by EGF, in which either phos-phorylated (p-EGFR) or total (EGFR) was showed by Western blot. This investigation may contribute to the further studies of cancer cells bearing EGFR.     

Glioblastoma—a moving target

Abstract

The slow development of effective treatment of glioblastoma is contrasted by the rapidly advancing research on the molecular mechanisms underlying the disease. Amplification and overexpression of receptor tyrosine kinases, particularly EGFR and PDGFRA, are complemented by mutations in the PI3K, RB1, and p53 signaling pathways. In addition to finding effective means to target these pathways, we may take advantage of the recent understanding of the hierarchical structure of tumor cell populations, where the progressive expansion of the tumor relies on a minor subpopulation of glioma stem cells, or glioma-initiating cells. Finding ways to reprogram these cells and block their self-renewal is one of the most important topics for future research.