表皮生长因子受体信号通路及其靶向肿瘤治疗

表皮生长因子受体(EGFR)属于蛋白酪氨酸激酶受体家族。在特异配体的刺激下，EGFR可激活P13K-Akt和Ras-Raf-MEK-ERK等多条信号通路。EGFR的异常高表达或突变可见于多种恶性肿瘤，并与肿瘤的恶性生物学行为和患者的不良预后密切相关。目前针对EGFR及其下游信号转导子已开发出多种抗肿瘤药物。这些药物疗效高，副作用小，具有良好的应用前景。     

表皮生长因子及其受体与肝癌的关系

EGF、EGFR具有广泛的生理作用，体内分布广泛，在肝癌的形成、复发及转移过程中，EGF、EGFR与Ca^2 通道、Na^ -H^ 通道、磷脂酰肌醇信息传递通道、基因表达异常、肿瘤血管及间质的形成关系密切，提示了治疗肝癌的新方向。现就EGF、EGFR与肝癌的形成、转移、复发的关系及其在临床中的应用前景作一综述。     

表皮生长因子及其受体与肝癌的关系

EGF、EGFR具有广泛的生理作用,体内分布广泛,在肝癌的形成、复发及转移过程中,EGF、EGFR与Ca2+通道、Na+-H+通道、磷脂酰肌醇信息传递通道、基因表达异常、肿瘤血管及间质的形成关系密切,提示了治疗肝癌的新方向.现就EGF、EGFR与肝癌的形成、转移、复发的关系及其在临床中的应用前景作一综述.     

乳腺癌EGF受体核素显像诊断和靶向治疗

目前临床上早期诊断及治疗乳腺癌的方法存在着各种局限性，非侵袭性表皮生长因子受体(EGFR)介导的放射性核素显像诊断及核素靶向治疗，以其独到的功能显像和分子治疗展示了未来乳腺癌早期定性诊断和微创治疗的美好前景。现综述乳腺癌EGFR核素显像诊断和核素靶向治疗的研究进展。     

表皮生长因子受体靶向肿瘤生物治疗

表皮生长因子受体(epidermal growth factor receptor,EGFR)的异常高表达可见于多种恶性肿瘤,并与肿瘤细胞的恶性生物学行为以及肿瘤患者的不良预后密切相关。EGFR已成为阳性表达肿瘤的重要治疗靶标。以EGFR为靶点的治疗主要有单克隆抗体以及小分子化合物激酶拮抗剂两种方式,目前已进行了广泛的实验与临床研究,其抗肿瘤的主要作用机制包括：(1)细胞周期阻滞;(2)促凋亡;(3)抗肿瘤浸润与转移;(4)抗新生血管生成;(5)放化疗细胞毒增敏。此外,本实验室曾以异种同源分子免疫的策略打破了机体对自身EGFR的免疫耐受,发现以人EGFR为免疫原在小鼠体内可以激发特异的免疫反应,该反应能交叉反应于鼠同源EGFR,进而达到治疗EGFR阳性表达肿瘤的目的。迄今,EGFR靶向治疗均很少观察到显著的EGFR相关的毒副作用,这可能与正常细胞EGFR显著的调控性低表达以及对EGFR通路信号的相对不依赖性相关。     

表皮生长因子及其受体与肿瘤

表皮生长因子及其受体与肿瘤第三军医大学新桥医院高全杰综述汪坤审校细胞生长分裂的调控，是一个十分复杂的过程．机体是由无数细胞组成的复杂社会，在多细胞生物中，细胞已失去单细胞生长的独立性，而置身于组织严密，互相制约的细胞群体的社会中．细胞“社会行为（Ｓｏ...     

靶向表皮生长因子受体的抗肿瘤治疗

表皮生长因子受体(EGFR)与恶性肿瘤的发生和发展密切相关.目前针对EGFR已经开发出多种单克隆抗体、酪氨酸激酶小分子抑制剂等药物应用于临床,在对多种晚期和耐药肿瘤的治疗中取得良好效果.     

以表皮生长因子受体为靶向的肿瘤信号转导干预治疗

表皮生长因子受体（EGFR）在相当一部分的人类肿瘤细胞存在高表达,且其所介导的信号转导与肿瘤的发生发展及预后密切相关,以其为靶子进行的肿瘤信号转导干预治疗是一种较佳的策略之一,为肿瘤治疗提供了可喜的前景。     

The epidermal growth factor receptor pathway: a model for targeted therapy.

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase receptor that is frequently expressed in epithelial tumors. The EGFR was the first receptor to be proposed as a target for cancer therapy, and after 2 decades of intensive research, there are several anti-EGFR agents available in the clinic. Recent advances in our understanding in the mechanisms of receptor activation and function, discovery of primary and secondary EGFR somatic mutations, as well as a new generation of anti-EGFR agents provide new leads on the clinical targeting of this receptor and may serve as a model for strategies aimed at targeting other receptors.     

人表皮生长因子受体2阳性胃癌靶向治疗的研究进展

以靶向治疗为代表的新兴治疗方法是传统一线放化疗耐药的有效补充,人表皮生长因子受体2（HER2）是胃癌靶向治疗中十分重要的靶点之一,曲妥珠单抗联合化疗已被用于晚期胃癌的一线治疗方案,帕妥珠单抗和马格妥昔单抗治疗胃癌的安全性和有效性已得到了验证。然而,单克隆抗体因其分子量较大、不能穿透血脑屏障,且耐药而导致治疗效果下降,因此需探索其他靶向HER2的疗法在胃癌中的疗效。小分子药物酪氨酸激酶抑制剂（TKI）如拉帕替尼、吡咯替尼等具有分子量小、可穿透血脑屏障和口服生物利用度高等优点,未来经过大型临床试验验证后有望成为胃癌围手术期治疗、新辅助治疗的选择药物。抗体-药物偶联物（ADC）如T-DM1、T-DXd等尽管其发挥肿瘤杀伤作用的机制不同,但能够克服单克隆抗体的耐药,是曲妥珠单抗等单抗治疗失败患者治疗药物的补充。因此,对胃癌患者进行更加细致的分层后,靶向HER2的各类胃癌治疗药物有望发挥更加显著的作用。     

Oncogenic fingerprint of epidermal growth factor receptor pathway and emerging epidermal growth factor receptor blockade resistance in colorectal cancer

Epidermal growth factor receptor (EGFR) has been an attractive target for treatment of epithelial cancers, including colorectal cancer (CRC). Evidence from clinical trials indicates that cetuximab and panitumumab (anti-EGFR monoclonal antibodies) have clinical activity in patients with metastatic CRC. The discovery of intrinsic EGFR blockade resistance in Kirsten RAS (KRAS)-mutant patients led to the restriction of anti-EGFR antibodies to KRAS wild-type patients by Food and Drug Administration and European Medicine Agency. Studies have since focused on the evaluation of biomarkers to identify appropriate patient populations that may benefit from EGFR blockade. Accumulating evidence suggests that patients with mutations in EGFR downstream signaling pathways including KRAS, BRAF, PIK3CA and PTEN could be intrinsically resistant to EGFR blockade. Recent whole genome studies also suggest that dynamic alterations in signaling pathways downstream of EGFR leads to distinct oncogenic signatures and subclones which might have some impact on emerging resistance in KRAS wild-type patients. While anti-EGFR monoclonal antibodies have a clear potential in the management of a subset of patients with metastatic CRC, further studies are warranted to uncover exact mechanisms related to acquired resistance to EGFR blockade.     

Coordinated epidermal growth factor receptor pathway gene overexpression predicts epidermal growth factor receptor inhibitor sensitivity in pancreatic cancer

The epidermal growth factor receptor (EGFR) inhibitor erlotinib is approved for treatment of pancreatic cancer but the overall activity is minimal, and known predictive factors for EGFR inhibitor efficacy are infrequent in this disease. We tested the hypothesis that global activation of the EGFR pathway is predictive of EGFR inhibitor efficacy. Pancreatic cancer tumors directly xenografted at surgery were treated with the EGFR inhibitors erlotinib and cetuximab and analyzed for biological features. Two of 10 tumors were sensitive, and by global gene expression profiling with gene set enrichment analysis, the EGFR pathway was highly expressed in sensitive compared with resistant tumors. The core gene components driving EGFR pathway overexpression were pathway ligands and positive effectors. In a prospective validation, the EGFR pathway-based signature correctly predicted anti-EGFR treatment response in eight additional tumors and was not predictive of response to gemcitabine and CI1040 (a MEK inhibitor). Analysis of EGFR, KRAS, and PIK3CA mutations and gene amplification by fluorescence in situ hybridization and multiplex ligation-dependent probe amplification showed that none of these genetic abnormalities were neither predictive nor responsible for the EGFR pathway activation. Coordinated overexpression of the EGFR pathway predicts susceptibility to EGFR inhibitors in pancreatic cancer. These results suggest a phenomenon of pathway addiction and support the value of unbiased system biology approaches in drug development.     

Human epidermal growth factor receptor 2 targeted therapy in endometrial cancer: Clinical and pathological perspectives

Endometrial cancer is the most common gynecological cancer in developed countries, and its incidence has increased. The majority of patients with endometrial cancer have an early disease and favorable prognosis; however, a significant proportion of endometrial cancer, which mainly comprises high-grade or type II endometrial cancer such as serous, clear cell, and carcinosarcoma, shows advanced/recurrent disease and dismal prognosis. Novel therapeutic development is required for patients with aggressive endometrial cancers. Recent genomic and immunohistochemical analyses revealed human epidermal growth factor receptor 2 (HER2) overexpression/gene amplification in 20%-40% of patients with type II endometrial cancer. Historically, HER2 targeted therapy has been developed for various major cancers, including breast and gastric cancer. Notably, recent advances in HER2 targeted therapy for patients with type II endometrial cancer are also expected to change. Simultaneously, an optimized HER2 test for endometrial cancer as companion diagnostics should be established. In this review, we summarize the recent findings on endometrial cancer, current treatment, optimized HER2 testing, key clinical trials on HER2 targeted therapy, and future directions in aggressive endometrial cancer, including serous carcinoma and carcinosarcoma.     

Can we predict the response to epidermal growth factor receptor targeted therapy?

Epidermal growth factor receptor (EGFR) targeted therapy interferes with a molecular pathway that significantly regulates tumor growth, progression, and survival. Several clinical trials on EGFR targeted therapy revealed objective responses, and also improved survival in patients with different solid tumors. However, considerable differences in therapeutic efficacy were recognized across patient populations that might rely on specific characteristics of the individual patient, the tumor dependence on the EGFR pathway or alternative signaling pathways. Therefore, molecular markers that predict responsiveness to the specific targeted therapy are essential. Predictive markers will help to identify which individual patients might benefit the most from targeted therapy, and thus will help to increase efficacy and decrease toxicities. The occurrence of an acne-like skin rash was the first clinical surrogate marker in EGFR targeted therapy significantly associated with response rate. In gastrointestinal cancer patients promising predictive molecular markers have now been identified within the EGFR signaling pathway. K-ras mutations are associated with resistance to EGFR monoclonal antibodies (mAbs) in metastatic colorectal cancer patients. Moreover, high gene expression levels of EGFR ligands amphiregulin and epiregulin are indicative for improved progression-free survival (PFS) in response to EGFR targeted therapy. Favorable response to EGFR targeted therapy has been correlated with low gene expression levels of vascular endothelial growth factor (VEGF). Furthermore, germline polymorphisms within the genes of epidermal growth factor (EGF) and EGFR, cyclooxygenase-2 (Cox-2), cyclin D1, and FCGR2A/3A are of predictive value. However, these first encouraging findings are limited mostly due to the small patient numbers evaluated in retrospective studies. Thus, large prospective clinical trials are needed to validate these data.     

Epidermal growth factor receptor dynamics influences response to epidermal growth factor receptor targeted agents

Analysis of gene expression of cancer cell lines exposed to erlotinib, a small molecule inhibitor of the epidermal growth factor receptor (EGFR), showed a marked increase in EGFR mRNA in resistant cell lines but not in susceptible ones. Because cetuximab induces EGFR down-regulation, we explored the hypothesis that treatment with cetuximab would interfere with erlotinib-induced EGFR up-regulation and result in antitumor effects. Exposure of the resistant biliary tract cancer cell line HuCCT1 but not the susceptible A431 epidermoid cell line to erlotinib induced EGFR mRNA and protein expression. Combined treatment with cetuximab blunted the erlotinib-induced EGFR up-regulation and resulted in inhibition of cell proliferation and apoptosis in the HuCCT1 cells. Blockage of erlotinib-induced EGFR synthesis in HuCCT1 cells by small interfering RNA resulted in identical antitumor effects as cetuximab, providing mechanistic specificity. In mice xenografted with A431, HuCCT1, and the pancreatic cancer cell line Panc430, maximal growth arrest and decrease in Ki67 proliferation index were documented with combined therapy, and EGFR down-regulation was observed in cetuximab-treated tumors. These results may indicate that resistance to EGFR kinase inhibition may be, at least in part, mediated by a highly dynamic feedback loop consisting of up-regulation of the EGFR upon exposure to EGFR kinase inhibitors. Abrogation of this response by small interfering RNA-mediated EGFR mRNA down-regulation and/or by cetuximab-mediated protein clearance induced tumor arrest across several cancer models with different EGFR expression levels, suggesting that resistance and sensitivity are dynamic events where proportional decrease in the target rather than absolute content dictates outcome.     

The epidermal growth factor receptor as a target for gastrointestinal cancer therapy

Opinion statement The epidermal growth factor receptor (EGFR) is a member of the family of transmem-brane protein kinase receptors known as the erbB or HER receptor family. When activated, EGFR phosphorylates and activates other intracellular proteins that affect cell signaling pathways, cellular proliferation, control of apoptosis and angiogenesis. EGFR signaling is best thought of as a network of activating and inactivating proteins with EGFR as the entry point into the network. EGFR overexpression occurs in most GI malignancies and while data are not entirely consistent, EGFR overexpression often confers a poor prognosis in those GI malignancies that have been studied. It often correlates with poorly differentiated histology, more advanced stage and other known poor prognostic markers. The EGFR is a tempting target because of its presence and overexpression on so many tumor types. However, downstream of the EGFR are several proteins that may be activated without EGFR thus allowing blockade to be overcome. Therefore, while blocking the activity of the EGFR protein appears to be a promising anticancer strategy, a simplistic strategy of blocking only EGFR is likely to only impact a minority of patients. It is time for the laboratory and clinical researchers to work closely together to develop this treatment strategy, moving back and forth from clini-cal to laboratory to best understand how to block this network effectively enough to produce a broader antitumor effect. While multiple methods of targeting the EGFR pathway are under development, including the inhibition of downstream proteins, only two modalities have entered clinical trials in GI malignancies: small molecule inhibitors of the intracellular kinase domain of EGFR and antibodies designed to block the extracellular ligand-binding domain of EGFR. EGFR inhibitors are still experimental in every GI malignancy with the notable exception of cetuximab that is approved for second or third-line therapy of metastatic colorectal cancer, used either alone or in combination with irinotecan (Camptosar, Kalamazoo, Mich). Data on clinical applications of these agents in GI malignancies will be the focus of this paper.