Radiosensitization of human breast cancer cells by a novel ErbB family receptor tyrosine kinase inhibitor

Purpose: Overexpression of the ErbB family of growth factor receptors is present in a wide variety of human tumors and is correlated with poor prognosis. The purpose of this study was to determine the effects of a novel small molecule ErbB tyrosine kinase inhibitor, CI-1033, in combination with ionizing radiation on breast cancer cell growth and survival.

Materials & Methods: Growth assays were performed on ErbB-overexpressing human breast cancer cells developed in our laboratory in the presence of 0.1–1.0 μM CI-1033 (Parke Davis). Clonogenic survival assays were performed in the presence of ionizing radiation with or without CI-1033. For some experiments, clonogen numbers, defined as the product of surviving fraction and total number of cells, were calculated at each time point during a course of multifraction radiation.

Results: CI-1033 potently inhibited the growth of ErbB-overexpressing breast cancer cells. A single 48-h exposure of 1 μM CI-1033 resulted in growth inhibition for 7 days, whereas three times weekly administration resulted in sustained growth inhibition. Clonogenic survival was modestly decreased after a 7-day exposure to CI-1033. Exposure to both CI-1033 and radiation (6 Gy) yielded a 23-fold decrease in clonogenic survival compared to radiation alone. In a multifraction experiment, exposure to CI-1033 and three 5-Gy fractions of gamma radiation decreased the total number of clonogens in the population by 65-fold compared to radiation alone.

Conclusion: CI-1033 results in potent growth inhibition and modest cytotoxicity of ErbB-overexpressing breast cancer cells, and has synergistic effects when combined with ionizing radiation. These data suggest that CI-1033 may have excellent clinical potential both alone and in combination with radiation therapy.     

Epidermal growth factor receptor tyrosine kinase inhibitors for non-small cell lung cancer

First-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib and erlotinib, have proven to be highly effective agents for advanced non-small cell lung cancer (NSCLC) in patients harboring an activating EGFR mutation such as the exon 19 deletion mutation and L858R. Although those reversible small molecular targeted agents provide a significant response and survival benefit, all responders eventually acquire resistance. Second-generation EGFR-targeting agents, such as irreversible EGFR/HER2 tyrosine kinase inhibitors and pan-HER TKIs, may improve survival further and be useful for patients who acquired resistance to first-generation EGFR-TKIs. This review discusses novel therapeutic strategies for EGFR-mutated advanced NSCLC using first- and second-generation EGFR-TKIs.     

EGFR tyrosine kinase inhibition radiosensitizes and induces apoptosis in malignant glioma and childhood ependymoma xenografts

Malignant gliomas and childhood ependymomas have a high rate of treatment failure. Epidermal growth factor receptor (EGFR) activation has been implicated in the tumorigenesis and radioresistance of many cancers, including brain tumors. Therefore, combining EGFR targeting with irradiation is a potentially attractive therapeutic option. We evaluated the tyrosine kinase inhibitor gefitinib for its antitumor activity and potential to radio-sensitize in vivo in two xenograft models: an EGFR amplified glioma and an EGFR expressing ependymoma, both derived from primary tumors. When administered at 100 mg/kg for 5 consecutive days, gefitinib-induced partial tumor regression in all treated EGFR amplified IGRG88 glioma xenografts. The addition of 1 Gy of irradiation prior to gefitinib administration resulted in 5 complete and 4 partial regressions for the 9 treated tumors as well as a significant tumor growth delay of 33 days for the combined treatment compared to 19 days for each therapy alone, suggesting additive antitumor activity. Tumor regression was associated with inhibition of AKT and MAPK pathways by gefitinib. In contrast, the ependymoma IGREP83 was sensitive to irradiation, but remained resistant to gefitinib. Combined treatment was associated with inhibition of radiation-induced MAPK phosphorylation and significant induction of apoptotic cell death though radiation-induced AKT phosphorylation was maintained. Depending on the scheduling of both therapies, a trend towards superior antitumor activity was observed with combined treatment. Thus, EGFR targeting through tyrosine kinase inhibition appears to be a promising new approach in the treatment of EGFR-driven glioma, particularly in combination with radiation therapy.     

Sensitivity of epidermal growth factor receptor and ErbB2 exon 20 insertion mutants to Hsp90 inhibition

The mature epidermal growth factor receptor (EGFR) neither associates with nor requires the molecular chaperone heat-shock protein 90 (Hsp90). Mutations in EGFR exons 18, 19, and 21 confer Hsp90 chaperone dependence. In non-small cell lung cancer (NSCLC), these mutations are associated with enhanced sensitivity to EGFR inhibitors in vitro and with clinical response in vivo. Although less prevalent, insertions in EGFR exon 20 have also been described in NSCLC. These mutations, however, confer resistance to EGFR inhibitors. In NSCLC, exon 20 insertions have also been identified in the EGFR family member ErbB2. Here, we examined the sensitivity of exon 20 insertion mutants to an Hsp90 inhibitor currently in the clinic. Our data demonstrate that both EGFR and ErbB2 exon 20 insertion mutants retain dependence on Hsp90 for stability and downstream-signalling capability, and remain highly sensitive to Hsp90 inhibition. Use of Hsp90 inhibitors should be considered in NSCLC harbouring exon 20 insertions in either EGFR or ErbB2.     

Trastuzumab-induced recruitment of Csk-homologous kinase (CHK) to ErbB2 receptor is associated with ErbB2-Y1248 phosphorylation and ErbB2 degradation to mediate cell growth inhibition

The inhibitory effect of trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of ErbB2, is associated with its ability to induce ErbB2-Y1248 phosphorylation, and the status of phosphorylated ErbB2-Y1248 (ErbB2-pY1248) may correlate with the sensitivity of breast cancers to trastuzumab. The mechanisms of which remain unclear. Here, we show that binding of trastuzumab to ErbB2 activates ErbB2 kinase activity and enhances ErbB2-Y1248 phosphorylation in trastuzumab-sensitive breast cancer cells. This in turn increases the interaction between ErbB2 and non-receptor Csk-homologous kinase (CHK), leading to growth inhibition of breast cancer cells. Overexpression of CHK mimics trastuzumab treatment to mediate ErbB2-Y1248 phosphorylation, Akt downregulation, and growth inhibition of trastuzumab-sensitive breast cancer cells. CHK overexpression combined with trastuzumab exerts an additive effect on cell growth inhibition. We further demonstrate that positive ErbB2-pY1248 staining in ErbB2-positive breast cancer biopsies correlates with the increased trastuzumab response in trastuzumab neoadjuvant settings. Collectively, this study highlights an important role for ErbB2-pY1248 in mediating trastuzumab-induced growth inhibition and trastuzumab-induced interactions between CHK and ErbB2-pY1248 is identified as a novel mechanism of action that mediates the growth inhibition of breast cancer cells. The novel mechanistic insights into trastuzumab action revealed by this study may impact the design of next generation of therapeutic monoclonal antibodies targeting receptor tyrosine kinases, as well as open new avenues to identify novel targets for the treatment of ErbB2-positive cancers.     

表皮生长因子受体酪氨酸激酶抑制剂ZD1839对鼻咽癌细胞系的作用

ZDl839是一种喹唑啉类化合物,它是一种口服的选择性的表皮生长因子受体酪氨酸激酶抑制剂,已被美国食品药品管理局批准用于治疗晚期非小细胞肺癌。鼻咽癌是一种存在表皮生长因子受体表达的上皮源性的恶性肿瘤,ZDl839对其作用如何还未见有报道。本实验通过体外研究初步探讨ZDl839在鼻咽癌治疗中的可能价值。     

姜黄素联合顺铂对非小细胞肺癌细胞A549放疗增敏作用的初步研究

目的 探讨姜黄素联合顺铂对非小细胞肺癌细胞A549放射增敏的影响。方法 采用MTT法观察不同浓度姜黄素（10、20、50、100、200 μmol/L）和顺铂（1、2、5、10、20 mg/L）作用24、48及72 h后的细胞存活率,根据实验设计分为单纯照射（R）组、姜黄素+照射（C+R）组、顺铂+照射（P+R）组及姜黄素+顺铂+照射（C+P+R）组,采用克隆形成实验检测4组经不同剂量X线（0、2、4、6、8、10 Gy）照射后的存活分数（SF）并通过单击多靶模型拟合细胞存活曲线计算增敏比（SER）,分别采用人工划痕、Transwell试验及Western blotting检测以上4组处理24 h后的细胞迁移、侵袭及表皮生长因子受体（EGFR）的蛋白水平。结果 随姜黄素（10~200 μmol/L范围内）和顺铂（1~20 mg/L范围内）浓度增加,A549细胞的细胞存活率降低,抑制效应呈浓度和时间依赖方式,差异有统计学意义（P<0.05）;C+P+R组在照射剂量为2~10 Gy时的细胞SF均低于其余3组,而C+R组在4~10 Gy,P+R组在2~10 Gy时的细胞SF均低于R组,差异有统计学意义（P<0.05）,C+R组、P+R组及C+P+R组相对于R组的SER依次为1.24、1.31和1.96;C+P+R组的迁移距离、穿膜细胞数量及EGFR蛋白水平均低于其余3组,而C+R组和P+R组的以上指标亦低于R组,以上差异均有统计学意义（P<0.05）。结论 姜黄素联合顺铂可抑制A549细胞增殖并具有放射增敏作用,同时抑制其迁移和侵袭,可能与EGFR相关信号通路受抑制有关。     

Current challenges and clinical investigations of epidermal growth factor receptor (EGFR)- and ErbB family-targeted agents in the treatment of head and neck squamous cell carcinoma (HNSCC)

Overexpression of the epidermal growth factor receptor (EGFR) is a common characteristic of head and neck squamous cell carcinomas (HNSCC). Cetuximab is a chimeric anti-EGFR monoclonal antibody (mAb) with multiple approved indications in HNSCC, including with radiation therapy (RT) for locoregionally advanced disease, as monotherapy after platinum progression, and with platinum/5-fluorouracil for recurrent or metastatic disease. There remain, however, numerous unanswered questions regarding the optimal use of cetuximab in HNSCC, including patient selection, its mechanisms of action and resistance, the effect of human papillomavirus status on outcomes, its role when combined with induction chemotherapy or adjuvant radiation, and optimal management of skin toxicity and hypersensitivity reactions. In addition, a variety of other anti-EGFR agents (the multitargeted small molecule tyrosine kinase inhibitors [TKIs] lapatinib, dacomitinib, and afatinib and the anti-EGFR mAbs zalutumumab, nimotuzumab, and panitumumab) are currently under investigation in phase II and III clinical trials in different HNSCC therapeutic settings. The anti-EGFR TKI erlotinib is currently in phase III development for oral cancer prevention. Numerous other drugs are in earlier stages of development for HNSCC treatment, including novel anti-EGFR mAbs (MEHD7945A, necitumumab, and RO5083945), small-molecule TKIs (vandetanib, icotinib, and CUDC-101), EGFR antisense, various add-on therapies to radiation and chemotherapy (bevacizumab, interleukin-12, lenalidomide, alisertib, and VTX-2337), and drugs (temsirolimus, everolimus, OSI-906, dasatinib, and PX-866) intended to overcome resistance to anti-EGFR agents. Overall, a wealth of clinical trial data is expected in the coming years, with the potential to modify significantly the approach to anti-EGFR therapy for HNSCC.     

Heregulin-induced activation of ErbB3 by EGFR tyrosine kinase activity promotes tumor growth and metastasis in melanoma cells

ErbB3 receptor tyrosine kinase has been shown to induce tumor progression in several types of cancer through heterodimerization with ErbB2. However, the role of ErbB3 and its ligand heregulin (HRG) in tumor metastasis remains poorly understood. In the present study, we tried to clarify their contributions to the metastasis of ErbB3-overexpressing B16-BL6 melanoma cells. Stimulation with HRG induced phosphorylation of ErbB3 and metastatic properties including MMP-9 expression, invasion, adhesion and experimental lung metastasis in vivo. These cellular responses were blocked by inhibiting the tyrosine kinase activity of EGFR with PD153035. In addition, phosphorylation of EGFR was rapidly induced by HRG, suggesting that EGFR is a possible heterodimeric counterpart of ErbB3. RNA interference demonstrated that subcutaneous tumor growth and angiogenesis was attenuated by inactivation of ErbB3 in cancer cells. Although experimental pulmonary metastasis was not affected by the knockdown of ErbB3, spontaneous metastasis was, even when primary tumors in the foot pad were amputated at a similar size. These results indicate that HRG-induced activation of ErbB3 via EGFR promotes tumor growth and metastasis of melanoma cells.     

EGFR mutation heterogeneity and the mixed response to EGFR tyrosine kinase inhibitors of lung adenocarcinomas

Background.

Non-small cell lung cancer patients with epidermal growth factor receptor (EGFR) mutations have mixed responses to tyrosine kinase inhibitors (TKIs). Intertumor heterogeneity in EGFR mutations is one potential explanation for this phenomenon.

Methods.

We performed direct sequencing to identify EGFR mutations in 180 pairs of lung adenocarcinoma samples (from 3,071 patients). The high-resolution melting method was used in discordant cases to confirm EGFR mutation status. Matching samples were divided into four groups: primary lesions detected at different times, primary tumors with matched metastatic lymph nodes, multiple pulmonary nodules, and primary tumors with matched distant metastases. Multivariate analyses were performed to evaluate correlations between heterogeneity and patient characteristics.

Results.

In the study population, the discordance rate was 13.9% (25 of 180). The multiple pulmonary nodules group had the highest discordance rate of 24.4% (10 of 41; odds ratio for heterogeneity in primary lesions detected at different times, 6.37; 95% confidence interval, 1.71–23.72; p = .006). Discordance rates in the metachronous and synchronous settings were 15.7% (22 of 140) and 7.5% (three of 40), respectively. In the 34 patients who developed EGFR TKI resistance, 10 (29.4%) cases exhibited heterogeneity and five (14.7%) patients exhibited a mixed response to the drug. Three (8.8%) of the patients with a mixed response also exhibited discordant EGFR mutations.

Conclusions.

The overall discordance rate of EGFR mutation heterogeneity in Asian patients with pulmonary adenocarcinoma is relatively low, but the rate in patients with multiple pulmonary nodules is significantly higher. This observation may explain the mixed tumor response to EGFR TKIs.     

Transactivation of epidermal growth factor receptor through platelet-activating factor/receptor in ovarian cancer cells

Background

We previously identified platelet-activating factor receptor (PAFR) as being overexpressed in ovarian cancer and found that its ligand PAF evoked EGFR phosphorylation using the phospho-antibody microarray. Epidermal growth factor receptor (EGFR) are also overexpressed in ovarian cancer and contribute to the growth of ovarian cancer cells. Here, we investigated the mechanisms of crosstalk between PAFR and EGFR signaling in ovarian cancer cells to further determine whether the interaction between PAFR and EGFR synergistic contribute to the progression of ovarian cancer.

Methods

Expression and localization of PAFR in several ovarian cancer cell lines were assessed by Western blot, realtime-PCR and immunofluorescence. The ovarian cancer cells were stimulated with PAF or PAF and in some experiments also pharmacological inhibitors. Phosphorylation of proteins in signaling pathways were measured by Western blot. HB-EGF concentrations of the supernatant from stimulated ovarian cancer cells were measured by enzyme-linked immunosorbent assay.

Results

Our data show that PAF increases EGFR phosphorylation through PAFR in a time- and dose- dependent manner in SKOV-3 ovarian cancer cells. This transactivation is dependent on phospholipase C-β and intracellular calcium signaling. This pathway is also Src tyrosine kinase- and metalloproteinase- dependent. PAF triggers EGFR activation through the increased heparin-binding EGF-like growth factor (HB-EGF) release in metalloprotease-dependent manner. Several studies involving EGFR transactivation through G-protein coupled receptor (GPCR) have demonstrated EGFR-dependent increase in ERK1/2 phosphorylation. Yet in SKOV-3 cells, PAF treatment also increases ERK1/2 phosphorylation in a EGFR-independent manner.

Conclusions

The results suggest that in SKOV-3 ovarian cancer cells, PAF transactivates EGFR and downstream ERK pathways, thus diversifying the GPCR-mediated signal. The crosstalk between PAFR and EGFR suggests a potentially important signaling linkage between inflammatory and growth factor signaling in ovarian cancer cells.     

The major vault protein mediates resistance to epidermal growth factor receptor inhibition in human hepatoma cells

To better understand the response of HCC to EGFR inhibition, we analyzed factors connected to the resistance of HCC cells against gefitinib. Sensitive HCC3 cells co-expressed EGFR and ErbB3 but lacked kinase-domain mutations in EGFR. Interestingly, expression of MVP was restricted to resistant cell lines, whereas ABCB1 and ABCC1 showed no association with gefitinib resistance. Moreover, ectopic MVP expression in HCC3 cells decreased gefitinib sensitivity, increased AKT phosphorylation and reduced the expression of inflammatory pathway-associated genes, whereas silencing of MVP in Hep3B and HepG2 cells increased sensitivity. These findings suggest MVP as a novel player in resistance against EGFR inhibition.     

选择性EGFR 酪氨酸激酶抑制剂吉非替尼对宫颈癌离体细胞的放射增敏作用

 目的 探讨表皮生长因子受体酪氨酸激酶抑制剂吉非替尼对宫颈癌离体细胞的放射增敏作用。方法 以宫颈鳞癌Siha细胞，腺癌HeLa细胞为研究对象，利用MTT法检测吉非替尼对Siha和HeLa细胞的增殖抑制作用；利用集落形成实验检测吉非替尼对Siha、HeLa细胞的放射增敏效应。结果 吉非替尼能够抑制Siha、HeLa细胞的增殖，其JC20，值分别是0．15μmol／L、0．32μmol／L，而且抑制作用呈剂量依赖性；吉非替尼作用于Siha、HeLa细胞72h后，放射增敏比SER分别为1．693、1．228。结论 吉非替尼对宫颈癌Siha、HeLa细胞具有明显的放射增敏作用。     

表皮生长因子受体活化与鼻咽癌患者无转移生存的关系

背景与目的:表皮生长因子受体(epidermal growth factor receptor,EGFR)在多种肿瘤中高表达,且与预后相关,然而,EGFR对鼻咽癌的预后价值尚存争议。本研究检测鼻咽癌组织中EGFR及其磷酸化形式(phosphorylated EGFR,pEGFR)的表达,探讨其与鼻咽癌预后的关系。方法:收集中山大学肿瘤防治中心1999年1月至12月住院治疗鼻咽癌患者的鼻咽癌组织110例,同时收集20例正常鼻咽组织。利用免疫组化方法检测鼻咽癌组织及正常鼻咽组织中EGFR及pEGFR的表达,半定量方法评价染色情况;采用单因素和多因素方法分析蛋白表达与临床病理特征及预后的关系。结果:EGFR及pEGFR在鼻咽癌组织和鼻咽正常组织的阳性率分别为100%(110/110)、10%(2/20)和60%(66/110)、15%(3/20),不同组织中两种蛋白表达的差异均具有统计学意义(P<0.001);EGFR蛋白高表达与T分期相关(P=0.034),而与其他临床病理特征无关。单因素分析显示pEGFR高表达患者5年无转移生存率显著低于pEGFR低表达患者(72.2%vs.91.0%,P=0.012),而多因素分析显示pEGFR表达不是鼻咽癌患者无转移生存的独立预后因素。结论:pEGFR高表达与鼻咽癌患者的无转移生存相关,EGFR活化可能与鼻咽癌的转移有关。     

EGFR基因突变与酪氨酸激酶抑制剂疗效及预后之间的关系

背景与目的已有的研究表明:表皮生长因子受体(epidermal growth factor receptor,EGFR)信号通路在非小细胞肺癌的发生和发展中起重要作用。EGFR酪氨酸激酶抑制剂(EGFR tyrosine kinase inhibitors,EGFR-TKIs)是目前非小细胞肺癌(NSCLC)治疗的热点。研究表明,EGFR基因突变与TKIs的疗效及预后相关。本研究旨在了解EGFR基因突变与两种酪氨酸激酶抑制剂疗效及预后的相关性。方法共收集了34例接受gefitinib单药治疗和25例接受erlotinib单药治疗的晚期NSCLC患者的病理组织蜡块及相关临床资料。用PCR-PAGE检测EGFR19外显子突变,PCR-RFLP检测EGFR21外显子突变,均用直接测序进行验证。结合临床进行分析。结果59例NSCLC标本中共检测出22例标本中有EGFR基因突变,突变率为37.3%。EGFR基因突变率在女性、腺癌、不吸烟患者中高(P<0.05)。有EGFR基因突变的患者接受酪氨酸激酶抑制剂治疗的有效率高于无突变患者(50%vs18.9%,P<0.05),疾病控制率高于无突变患者(86.4%vs54.1%,P<0.05)。有EGFR基因突变的患者的疾病进展时间和总生存期均高于无突变患者,但是没有统计学差异(P>0.05)。结论EGFR基因突变在女性、腺癌和不吸烟者中发生率高。有EGFR基因突变的晚期NSCLC接受EGFR酪氨酸激酶抑制剂治疗的有效率和疾病控制率高于无EGFR基因突变者。     

表皮生长因子受体酪氨酸激酶抑制剂的研究进展

表皮生长因子受体(epidermal growth factor receptor,EGFR)在细胞的信号转导、细胞增殖和分化中发挥着重要的作用,对多种肿瘤的发生和发展也具有重要影响,抑制该受体活性可以有效抑制肿瘤的生长。以此为靶点的抗肿瘤药物的开发,在多种肿瘤治疗中取得了令人鼓舞的疗效。     

Induction of cell cycle arrest and apoptosis in human nasopharyngeal carcinoma cells by ZD6474, an inhibitor of VEGFR tyrosine kinase with additional activity against EGFR tyrosine kinase

ZD6474 is a vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. The present study was undertaken to investigate the direct antiproliferative effect of ZD6474 on human nasopharyngeal carcinoma (NPC) in vitro and the antitumor activity on NPC xenografts in vivo. Results indicated that ZD6474 treatment inhibited EGFR phosphorylation and led to a dose- and time-dependent decrease in NPC cell (CNE-1, CNE-2 and C666-1) proliferation. Further investigation demonstrated G0/G1 cell cycle arrest in all 3 cell lines, which was associated with an upregulation of p21 and/or p27, and downregulation of CDK4, CDK6 and CDK2. ZD6474 treatment also induced apoptosis in CNE-1 and CNE-2 cells. The apoptosis mechanisms involved reduction of Bcl-2 and/or Bcl-XL, induction of Bak and/or Bax, and activation of caspases-3, -9 and/or -8. The in vivo antitumor activity was evaluated in CNE-2 and C666-1 xenografted nude mice. Administration of ZD6474 (25-100 mg/kg/day, once-daily, p.o.) produced a dose-dependent inhibition of tumor growth and prolonged survival in both models. This study suggests that ZD6474 exerts direct antiproliferative effects on NPC cell lines in vitro by inducing G0/G1 arrest and apoptosis, and potent antitumor effects on NPC xenografts in vivo. It indicates that ZD6474 may offer a new and effective treatment for human NPC.     

Epidermal growth factor competes with EGF receptor inhibitors to induce cell death in EGFR-overexpressing tumor cells

Epidermal growth factor receptor (EGFR) signaling plays an important role in cell growth and differentiation. Mutations in the EGFR gene and EGFR gene amplifications have been associated with increased responsiveness to selective EGFR tyrosine kinase inhibitors (EGFR-TKIs). By contrast, EGF may also stimulate apoptosis in tumor cells, depending on EGFR and Her2 (erbB-2) expression levels. In the present study, we investigated cellular responses after EGFR activation by EGF, or inhibition by cetuximab and gefitinib. EGF treatment induced a near-immediate increase in p38 MAPK phosphorylation together with inactivation of ERK1/2. In contrast, gefitinib- and cetuximab-induced phosphorylation of p38 MAPK was much delayed, and gefitinib also induced a delayed activation of ERK1/2. EGF induced progressive cell death of A431 cells with prolonged treatment, whereas cetuximab- or gefitinib-treated cells showed temporary growth arrest and subsequent re-growth. Moreover, in combination treatment experiments, cetuximab or gefitinib competitively inhibited EGF-induced cell death. Normal WI38-VA13 cells did not display any noticeable changes in cell proliferation in response to EGF, gefitinib or cetuximab. EGF-induced death signaling is apparently irreversible: EGF induced significant EGFR phosphorylation/internalization and activated caspase-3, -8 and -9, effects that were not observed in cetuximab- or gefitinib-treated cells. Collectively, these results indicate that EGF may be a more potent cytotoxic agent than EGFR blockers in EGFR-overexpressing cancer cells.     

表皮生长因子受体酪氨酸激酶抑制剂的研究进展

表皮生长因子受体（epidermal growth factor receptor，EGFR）在细胞的信号转导、细胞增殖和分化中发挥着重要的作用，对多种肿瘤的发生和发展也具有重要影响，抑制该受体活性可以有效抑制肿瘤的生长。以此为靶点的抗肿瘤药物的开发，在多种肿瘤治疗中取得了令人鼓舞的疗效。