小分子酪氨酸激酶抑制剂治疗非小细胞肺癌研究进展

介绍小分子酪氨酸激酶抑制剂(埃罗替尼和吉非替尼)的作用机制,单药治疗及和化疗药联合治疗的临床试验,探讨化疗、放疗、表皮生长因子受体表达及突变、患者的临床特点等因素与小分子酪氨酸激酶抑制剂临床疗效的关系,阐述小分子酪氨酸激酶抑制剂治疗非小细胞肺癌的进展。     

表皮生长因子受体抑制剂在非小细胞肺癌治疗中的应用

特异性阻断肿瘤生长的表皮生长因子受体(EGFR)抑制剂在非小细胞肺癌(NSCLC)的治疗中具有极大潜力。目前,有两种通过修正细胞内外酪氨酸激酶信号传导过程来达到阻断此信号传导通路的治疗方法已被应用于NSCLC的治疗中。现以吉非替尼、西妥昔单抗等药物为例,综述EGFR抑制剂在NSCLC治疗中单独及与化疗或其他靶向治疗药物联合应用的临床研究进展。     

埃罗替尼在非小细胞肺癌治疗中的研究进展

埃罗替尼(erlotinib)是表皮生长因子受体(EGFR)酪氨酸激酶抑制剂,能与细胞内EGFR分子酪氨酸激酶结构域的ATP结合袋特异性结合,可逆性地抑制EGFR酪氨酸激酶活性,促使肿瘤细胞凋亡,抑制肿瘤细胞的增殖、侵袭、血管新生和转移。该药目前已成功用于晚期非小细胞肺癌(NSCLC)的治疗,可显著延长患者的生存时间和无进展生存时间,显著改善症状,改善患者生活质量。     

吉非替尼治疗非小细胞肺癌研究进展

表皮生长因子受体(EGFR)是一种受体型酪氨酸激酶,在非小细胞肺癌中过表达或突变,通过其下游的信号传导通路,促进细胞的增殖和血管形成,同时抑制肿瘤细胞凋亡.因此,选择性地抑制表皮生长因子受体介导的信号传导途径以达到肿瘤治疗的目的已成为近年来研究的热点.其中研究较多的是酪氨酸酶抑制剂吉非替尼,本文从吉非替尼的作用机制和临床应用,对吉非替尼敏感的非小细胞肺癌患者的筛选,吉非替尼的获得性耐药问题这三个方面,对近年来的研究综述如下.     

埃罗替尼在非小细胞肺癌治疗中的研究进展

埃罗替尼（erlotinib）是表皮生长因子受体（EGFR）酪氨酸激酶抑制剂，能与细胞内EGFR分子酪氨酸激酶结构域的ATP结合袋特异性结合，可逆性地抑制EGFR酪氨酸激酶活性，促使肿瘤细胞凋亡，抑制肿瘤细胞的增殖、侵袭、血管新生和转移。该药目前已成功用于晚期非小细胞肺癌（NSCLC）的治疗，可显著延长患者的生存时间和无进展生存时间，显著改善症状，改善患者生活质量。     

吉非替尼在非小细胞肺癌治疗中耐药机制的研究进展

吉非替尼(gefitinib)是表皮生长因子受体(epidermal growth factor receptor,EGFR)酪氨酸激酶抑制剂类靶向药物,与传统化疗药物相比,从细胞受体、增值调控的分子水平对肿瘤发病机制进行调控的靶向药物吉非替尼可使EGFR突变阳性患者的无疾病进展生存期显著延长。     

表皮生长因子受体抑制剂在非小细胞肺癌治疗中的应用

特异性阻断肿瘤生长的表皮生长因子受体（EGFR）抑制剂在非小细胞肺癌（NSCLC）的治疗中具有极大潜力。目前，有两种通过修正细胞内外酪氨酸激酶信号传导过程来达到阻断此信号传导通路的治疗方法已被应用于NSCLC的治疗中。现以吉非替尼、西妥昔单抗等药物为例，综述EGFR抑制剂在NSCLC治疗中单独及与化疗或其他靶向治疗药物联合应用的临床研究进展。     

吉非替尼治疗非小细胞肺癌研究进展

表皮生长因子受体（EGFR）是一种受体型酪氨酸激酶,在非小细胞肺癌中过表达或突变,通过其下游的信号传导通路,促进细胞的增殖和血管形成,同时抑制肿瘤细胞凋亡。因此,选择性地抑制表皮生长因子受体介导的信号传导途径以达到肿瘤治疗的目的已成为近年来研究的热点。其中研究较多的是酪氨酸酶抑制剂吉非替尼,本文从吉非替尼的作用机制和临床应用,对吉非替尼敏感的非小细胞肺癌患者的筛选,吉非替尼的获得性耐药问题这三个方面,对近年来的研究综述如下。     

厄罗替尼靶向治疗肿瘤临床研究进展

表皮生长因子受体（epidermal growth factor receptor,EGFR）是跨膜酪氨酸激酶受体,许多上皮肿瘤均有表达。厄罗替尼是喹唑啉类衍生物,可以选择性、可逆的抑制EGFRTK的活性。本文对厄罗替尼治疗非小细胞肺癌、胰腺癌、头颈部癌进行了综述。     

IGF-1R抑制剂联用可增强人非小细胞肺癌PC9/G细胞对吉非替尼的敏感性

目的:观察单用表皮生长因子受体(epidermal growth factor receptor, EGFR)的酪氨酸激酶抑制剂吉非替尼 (ge? tinib) 或联合胰岛素生长因子-1受体(insulin-like growth factor-1 receptor,IGF-1R)的酪氨酸激酶抑制剂AG1024作用于人非小细胞肺癌耐药株PC9/G细胞后,该细胞对吉非替尼耐药性的影响,并探讨IGF-1R与肿瘤细胞耐药的相关机制。方法:用吉非替尼和AG1024单独或联合作用于PC9/G细胞后,采用MTT法分别检测各组细胞的增殖情况,并利用中效原理判断两药联用的效果;FCM法检测各组细胞的凋亡情况;Western印迹法检测各组细胞的磷酸化EGFR(phosphorylated EGFR, p-EGFR)、磷酸化Akt(phosphorylated Akt,p-Akt)和磷酸化细胞外信号调节激酶(phosphorylated extracellular signal-regulated kinase,p-ERK)的表达水平。结果:吉非替尼和AG1024单独作用于PC9/G细胞后,均出现不同程度的细胞增殖抑制作用和细胞凋亡促进作用;而吉非替尼和AG1024联合作用,能更显著地抑制细胞增殖,且凋亡细胞显著增加(P<0.05)。 Western印迹法检测发现,联合用药组的p-EGFR、p-Akt和p-ERK蛋白表达量明显减少。结论:IGF-1R抑制剂AG1024和EGFR抑制剂吉非替尼联用具有较好的协同作用,可能通过抑制细胞增殖和促进细胞凋亡,提高耐药细胞对吉非替尼的敏感性。     

Targeting HER1/EGFR in cancer therapy: experience with erlotinib

Research into the role of the human epidermal receptor growth factor receptor 1/epidermal growth factor receptor (HER1/EGFR) in tumorigenesis has generated a new class of anticancer drugs. One such agent, erlotinib (Tarceva), is a potent, selective and reversible inhibitor of HER1/EGFR tyrosine kinase activity. Erlotinib has demonstrated the clinical activity in a variety of solid tumors, and has recently demonstrated improvements in survival in large Phase III trials, in non-small-cell lung cancer and pancreatic cancer.     

Does erlotinib restore chemosensitivity to chemotherapy in pancreatic cancer? A case series

Erlotinib (Tarceva) in combination with gemcitabine is indicated for first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer. In preclinical models, exposure of pancreatic cancer cell lines to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor plus gemcitabine suggested enhanced cytotoxicity of gemcitabine and induced apoptosis in tumor cells. Erlotinib inhibited gemcitabine-induced phosphorylation of EGFR, which may promote cytotoxicity from gemcitabine. The effectiveness of the combination of irinotecan and cetuximab in patients with irinotecan-refractory colon cancer tumors suggests that cetuximab may circumvent irinotecan resistance. This report describes the author's experience with the use of erlotinib in patients with pancreatic cancer and discusses the possible role of erlotinib in restoring chemosensitivity in pancreatic cancer.     

Erlotinib (Tarceva): a promising drug targeting epidermal growth factor receptor tyrosine kinase

Overexpression of the epidermal growth factor receptor (EGFR) is correlated with a poor prognosis in several human malignancies. In addition, cancers overexpressing EGFR respond poorly to both chemotherapy and radiation therapy. Therefore, EGFR is a viable target for cancer therapy. This review will address how EGFR blockade modulates signal transduction, leading to alterations in the cell cycle progression with secondary inhibition of proliferation and differentiation of cancer cells. As a prototypical example, erlotinib (Tarceva), a reversible EGFR tyrosine kinase inhibitor will be discussed. This drug has demonstrated promising antitumor activity in Phase II trials in several solid tumors and definitive Phase III studies to demonstrate clinical benefit have completed accrual.     

Targeting epidermal growth factor receptor: novel therapeutics in the management of cancer

Overexpression of epidermal growth factor receptor (EGFR) in epithelial tumors, including head and neck, lung, breast, colon and other solid tumors, has frequently been correlated with poor prognosis, thus stimulating efforts to develop new cancer therapies that target EGFR. Monoclonal antibodies and tyrosine kinase inhibitors specifically targeting EGFR are the most well-studied and hold substantial promise of success. Several compounds of monoclonal antibodies and tyrosine kinase inhibitors targeting EGFR have been studied and clinical trials are now underway to test the safety and efficacy of these targeting strategies in several human tumors. This review will address each of these agents alone or in combination with radiation or chemotherapy and highlight some of these promising developments. Cetuximab (Erbitux) is being evaluated in combination with radiation or chemotherapy in Phase III trials. Other compounds such as h-R3, ABX-EGF, EMD-55900 and ICR-62 have proved to be effective in targeting malignant cells alone or in combination with traditional therapies. Tyrosine kinase inhibitors targeting the intracellular domain of EGFR, including ZD-1839 (gefitinib, Iressa), OSI-774 (Erlotinib/Tarceva), PD-153053, PD-168393 and CI-1033, have been studied in clinical setting alone or in combination with radiation or chemotherapy. ZD-1839 is being studied in a Phase III trial in patients with advanced non-small cell lung cancer. EGFR targeted treatment by monoclonal antibodies and tyrosine kinase inhibitors have been proven to sensitize tumor cells to the effects of chemotherapy and radiation therapy. The synergistic activities and nonoverlapping toxicities of these compounds allow concomitant administration with cytotoxic therapy. Challenges of evaluating EGFR targeted agents exist in selecting the optimal dosages and determining long-term toxicity.     

Current knowledge and future directions of the selective epidermal growth factor receptor inhibitors erlotinib (Tarceva) and gefitinib (Iressa)

Gefitinib (Iressa); AstraZeneca Pharmaceuticals, Wilmington, DE, http://www.astrazeneca-us.com) and erlotinib (Tarceva); OSI Pharmaceuticals, Inc., Melville, NY, http://www.osip.com) are so-called small molecules that selectively inhibit epidermal growth factor receptor (EGFR) tyrosine kinase activity. Both drugs received registration approval by the U.S. Food and Drug Administration (FDA) for the second- and third-line treatment of non-small cell lung cancer (NSCLC), but the failure of gefitinib to show a survival advantage over placebo has resulted in a discussion about the registration of gefitinib. Recently published results have revealed that mutations in the tyrosine kinase domain of EGFR are strongly associated with increased gefitinib and erlotinib sensitivity in patients with advanced NSCLC. Here, we present the current knowledge and the future directions of the EGFR tyrosine kinase inhibitors gefitinib and erlotinib.     

Enhanced sensitivity to the HER1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib hydrochloride in chemotherapy-resistant tumor cell lines.

PURPOSE: Erlotinib (Tarceva, OSI-774) is a potent and specific inhibitor of the HER1/epidermal growth factor receptor (EGFR) tyrosine kinase. In phase II clinical studies, oral erlotinib monotherapy has shown antitumor activity in patients with advanced non-small cell lung cancer, head and neck cancer, and ovarian cancer after the failure of standard chemotherapy. We hypothesized that some tumors treated with multiple cytotoxic therapies may become more dependent on the HER1/EGFR signaling pathways for survival. EXPERIMENTAL DESIGN: The growth-inhibitory effect of erlotinib was tested on 10 pairs of chemosensitive, parental, and chemoresistant tumor cell lines. RESULTS: Enhanced sensitivity to erlotinib was observed in the doxorubicin-resistant human breast cancer cell line MCF-7, paclitaxel-resistant human ovarian carcinoma cell line A2780, and cisplatin-resistant human cervical carcinoma cell line ME180. The IC(50) values of erlotinib in the resistant cell lines were 2- to 20-fold lower than those in the corresponding parental cell lines. This enhanced sensitivity to erlotinib correlated with higher HER1/EGFR and phospho-HER1/EGFR expression when compared with the corresponding parental cell lines. Acquired resistance to cytotoxic agents was not associated with cross-resistance to erlotinib. AE-ME180/CDDP-resistant xenografts showed greater sensitivity to erlotinib than parental ME180 xenografts did. CONCLUSIONS: Our findings suggest that acquired resistance to cytotoxic therapy in some tumors is associated with enhanced sensitivity to HER1/EGFR inhibitors, which correlates with increased HER1/EGFR expression. These data may explain some of the observed clinical activity of HER1/EGFR inhibitors in patients previously treated with multiple therapies. HER1/EGFR tyrosine kinase inhibitors may be more effective as second- or third-line treatment for certain patients with tumors that were previously treated with multiple chemotherapy regimens.     

非小细胞肺癌中EGFR基因状态的检测对EGFR-TKIs疗效的预测价值

近几年,表皮生长因子受体(epidermal growth factor receptor,EGFR)是肿瘤学药物研发的一个重要靶点。EGFR的小分子抑制剂(tyrosine kinase inhibitors,TKIs)成为目前非小细胞肺癌(non-small cell lung cancer,NSCLC)靶向治疗的热点。临床研究表明,EGFR-TKIs的临床疗效存在明显的个体差异,EGFR分子的存在状态影响TKI的疗效。EGFR外显子突变、EGFR拷贝数增加的患者对TKI的疗效较好,而存在KRAS突变患者提示对TKI耐药。     

A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells

GW572016 (Lapatinib) is a tyrosine kinase inhibitor in clinical development for cancer that is a potent dual inhibitor of epidermal growth factor receptor (EGFR, ErbB-1) and ErbB-2. We determined the crystal structure of EGFR bound to GW572016. The compound is bound to an inactive-like conformation of EGFR that is very different from the active-like structure bound by the selective EGFR inhibitor OSI-774 (Tarceva) described previously. Surprisingly, we found that GW572016 has a very slow off-rate from the purified intracellular domains of EGFR and ErbB-2 compared with OSI-774 and another EGFR selective inhibitor, ZD-1839 (Iressa). Treatment of tumor cells with these inhibitors results in down-regulation of receptor tyrosine phosphorylation. We evaluated the duration of the drug effect after washing away free compound and found that the rate of recovery of receptor phosphorylation in the tumor cells reflected the inhibitor off-rate from the purified intracellular domain. The slow off-rate of GW572016 correlates with a prolonged down-regulation of receptor tyrosine phosphorylation in tumor cells. The differences in the off-rates of these drugs and the ability of GW572016 to inhibit ErbB-2 can be explained by the enzyme-inhibitor structures.     

Antitumor activity of ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, in human cancer cells with acquired resistance to antiepidermal growth factor receptor therapy.

PURPOSE: The epidermal growth factor receptor (EGFR) autocrine signaling pathway is involved in cancer development and progression. EGFR inhibitors such as C225 (cetuximab), a chimeric human-mouse anti-EGFR monoclonal antibody, and ZD1839 (gefitinib), a small molecule EGFR-selective tyrosine kinase inhibitor, are in advanced clinical development. The potential emergence of cancer cell resistance in EGFR-expressing cancers treated with EGFR inhibitors could determine lack of activity of these drugs in some cancer patients. Vascular endothelial growth factor (VEGF) is secreted by cancer cells and plays a key role in the regulation of tumor-induced endothelial cell proliferation and permeability. ZD6474 is a small molecule VEGF flk-1/KDR (VEGFR-2) tyrosine kinase inhibitor that also demonstrates inhibitory activity against EGFR tyrosine kinase. EXPERIMENTAL DESIGN: The antitumor activity of ZD1839, C225, and ZD6474 was tested in athymic mice bearing human GEO colon cancer xenografts. GEO cell lines resistant to EGFR inhibitors were established from GEO xenografts growing in mice treated chronically with ZD1839 or C225. Expression of EGFR was evaluated by flow cytometry. Expression of various proteins involved in intracellular cell signaling was assessed by Western blotting. Tumor growth data were evaluated for statistical significance using the Student's t test. All Ps were two-sided. RESULTS: Although chronic administration of optimal doses of C225 or ZD1839 efficiently blocked GEO tumor growth in the majority of mice, tumors slowly started to grow within 80-90 days, despite continuous treatment. In contrast, continuous treatment of mice bearing established GEO xenografts with ZD6474 resulted in efficient tumor growth inhibition for the entire duration of dosing (up to 150 days). ZD6474 activity was also determined in mice pretreated with ZD1839 or C225. When GEO growth was apparent after 4 weeks of treatment with EGFR inhibitors, mice were either re-treated with EGFR inhibitors or treated with ZD6474. GEO tumor growth was blocked only in mice treated with ZD6474, whereas tumor progression was observed in mice re-treated with C225 or ZD1839. GEO tumors growing during treatment with C225 or with ZD1839 were established as cell lines (GEO-C225-RES and GEO-ZD1839-RES, respectively). Cell membrane-associated EGFR expression was only slightly reduced in these cell lines compared with parental GEO cells. Western blotting revealed no major change in the expression of the EGFR ligand transforming growth factor alpha of bcl-2, bcl-xL, p53, p27, MDM-2, akt, activated phospho-akt, or mitogen-activated protein kinase. However, both GEO-C225-RES and GEO-ZD1839-RES cells exhibited a 5-10-fold increase in activated phospho-mitogen-activated protein kinase and in the expression of cyclooxygenase-2 and of VEGF compared with GEO cells. GEO-C225-RES and GEO-ZD1839-RES growth as xenografts in nude mice was not significantly affected by treatment with either C225 or ZD1839 but was efficiently inhibited by ZD6474. CONCLUSIONS: Long-term treatment of GEO xenografts with selective EGFR inhibitors results in the development of EGFR inhibitor-resistant cancer cells. Growth of EGFR inhibitor-resistant tumors can be inhibited by ZD6474. These data indicate that inhibition of VEGF signaling has potential as an anticancer strategy, even in tumors that are resistant to EGF inhibitors.     

New drug development in digestive neuroendocrine tumors.

The traditional cytotoxic agents are of limited efficacy in the treatment of neuroendocrine tumors of the gastrointestinal tract (NETs). Recent investigations have brought up a number of biological features in this family of neoplasms that could represent targets for anticancer treatment. NETs seem to have an extraordinary tumor vascularization with high expression of proangiogenic molecules such as the vascular endothelial growth factor along with overexpression of certain tyrosine kinase receptors such as the epidermal growth factor receptor (EGFR), the insulin growth factor receptor (IGFR) and their downstream signaling pathway components (PI3K-AKT-mTOR). The rationale of an antiangiogenic approach in the treatment of NETs and the use of other pharmacological strategies such as EGFR, IGFR and mammalian target of rapamycin inhibitors are discussed. Additionally, the emerging results of recent clinical trials with these targeted drugs are presented.