表皮生长因子受体酪氨酸激酶抑制剂耐药后非小细胞肺癌治疗研究进展

表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor-tyrosine kinease inhibitors ,EGFR-TKIs）对EGFR 敏感突变非小细胞肺癌（non small cell lung cancer,NSCLC ）除了其卓越的疗效,也如其他药物一样最终不可避免地发生耐药。EGFR 基因突变是最常见的肺癌驱动基因之一,针对 EGFR-TKI 耐药后的处理,目前虽无固定治疗模式,但临床进行了大量的探索性研究及治疗对策的探讨,部分结果对临床治疗这类患者有一定启示。本文将就近年具有代表性的研究及进展做一论述。     

Management of acquired resistance to epidermal growth factor receptor kinase inhibitors in patients with advanced non‐small cell lung cancer

The widespread adoption of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors for the first‐line treatment of patients with advanced EGFR‐mutated non‐small cell lung cancer has resulted in acquired tyrosine kinase inhibitor resistance becoming a ubiquitous clinical problem. The identification of specific mechanisms of acquired resistance has allowed a better understanding of the biology and natural history of resistant disease, but is only now starting to impact treatment decisions. Strategies for managing acquired resistance in patients with advanced non‐small cell lung cancer are complex and must be adapted to the individual characteristics of each patient's cancer. Although combination chemotherapy is the presumed standard of care for most patients, prospective trial data are lacking, highlighting the importance of offering patients participation in clinical trials in this setting. Emerging data from trials of third‐generation mutant‐specific EGFR kinase inhibitors suggests particular promise with this class of agents. Cancer 2014;120:2289–2298. © 2014 American Cancer Society.     

244-MPT overcomes gefitinib resistance in non-small cell lung cancer cells

The epidermal growth factor receptor (EGFR) is known to play a critical role in non-small cell lung cancer(NSCLC). Several EGFR tyrosine kinase inhibitors(TKIs), such as gefitinib, have been used as effective clinical therapies for patients with NSCLC. Unfortunately, acquired resistance to gefitinib commonly occurs after 6–12 months of treatment. The resistance is associated with the appearance of the L858R/T790M double mutation of the EGFR. In our present study, we discovered a compound,referred to as 244-MPT, which could suppress either gefitinib-sensitive or -resistant lung cancer cell growth and colony formation, and also suppressed the kinase activity of both wildtype and double mutant (L858R/T790M) EGFR. The underlying mechanism reveals that 244-MPT could interact with either the wildtype or double-mutant EGFR in an ATP-competitive manner and inhibit activity. Treatment with 244-MPT could substantially reduce the phosphorylation of EGFR and its downstream signaling pathways, including Akt and ERK1/2 in gefitinib-sensitive and -resistant cell lines. It was equally effective in suppressing EGFR phosphorylation and downstream signaling in NL20 cells transfected with wildtype, single-mutant (L858R) or mutant (L858R/T790M) EGFR. 244-MPT could also induce apoptosis in a gefitinib-resistant cell line and strongly suppress gefitinib-resistant NSCLC tumor growth in a xenograft mouse model. In addition, 244-MPT could effectively reduce the size of tumors in a gefitinib-resistant NSCLC patient-derived xenograft (PDX) SCID mouse model. Overall, 244-MPT could overcome gefitinib-resistance by directly targeting the EGFR.     

B细胞淋巴瘤/白血病-2在非小细胞肺癌中的表达与表皮生长因子受体抑制剂获得性耐药的关系

目的探讨非小细胞肺癌(NSCLC)患者在表皮生长因子受体(EGFR)抑制剂治疗发生耐药前后肺癌组织标本中B细胞淋巴瘤/白血病(bcl-2)表达的变化,明确bcl-2表达与EGFR抑制剂获得性耐药的关系。方法收集北京大学深圳医院2004年至2011年经吉非替尼片或盐酸厄洛替尼片治疗的23例NSCLC患者的系列肺癌组织标本。建立组织芯片,以免疫组化的方法检测bcl-2的表达情况,同时比较产生耐药前后bcl-2表达的变化。结果 23例标本耐药前bcl-2表达阳性例数为5例,阳性率为21.7%。耐药后bcl-2表达阳性例数为12例,阳性率为52.2%。两者比较,差异有统计学意义(X2=4.57,P=0.032)。表皮生长因子酪氨酸激酶抑制剂(EGFR-TKI)治疗后出现获得性耐药的患者,bcl-2较耐药前出现明显上调。结论 bcl-2介导的抗凋亡功能增强在EGFR-TKI获得性耐药的发生中可能起到了重要作用。     

晚期非小细胞肺癌患者使用EGFR-TKI治疗后长期生存的研究

目的 探索应用表皮生长因子受体酪氨酸激酶抑制剂( EGFR-TKI)治疗晚期非小细胞肺癌(NSCLC)患者长期生存的影响因素,并研究长期生存者与EGFR突变关系.方法回顾性分析2002年12月至2007年6月在北京协和医院进行EGFR-TKI治疗的292例晚期NSCLC,并收集长期生存(定义为使用吉非替尼或厄洛替尼治疗...     

EGFR-TKI治疗非小细胞肺癌的耐药机制进展研究

肺癌的发病率和死亡率已居我国恶性肿瘤的第一位。以表皮生长因子受体,酪氨酸激酶为靶点的酪氨酸激酶抑制剂(EGFR-TKI)治疗肺癌已广泛引起关注。但部分患者在服用EGFR-TKI初期即出现原发耐药,有些患者在服用EGFR-TKI一段时间后产生继发性耐药,本文综述EGFR-TKl分子耐药机制的研究现状,探讨EGFR-TKl分子耐药机制重要的临床意义。      

ＥＧＦＲ-ＴＫＩｓ获得性耐药及耐药后治疗的进展

表皮生长因子受体酪氨酸激酶抑制剂（ＥＧＦＲ-ＴＫＩｓ）吉非替尼和厄洛替尼是用于化疗后失败或复发的晚期非小细胞肺癌的常用药物,随着对它们的深入研究,发现ＥＧＦＲ-ＴＫＩｓ的疗效与ＥＧＦＲ突变相关。然而,几乎所有接受ＥＧＦＲ-ＴＫＩｓ治疗的患者都会出现耐药,而获得性耐药后目前没有标准治疗方案。本文主要探讨ＥＧＦＲ-ＴＫＩｓ获得性耐药的定义,并对目前克服获得性耐药的临床研究作一综述。     

Effect of EGFR-TKI retreatment following chemotherapy for advanced non-small cell lung cancer patients who underwent EGFR-TKI

Objective： Non-small cell lung cancer （NSCLC） patients with epidermal growth factor receptor （EGFR）-activating mutations have higher response rate and more prolonged survival following treatment with single-agent EGFR tyrosine kinase inhibitor （EGFR-TKI） compared with patients with wild-type EGFR. However, all patients treated with reversible inhibitors develop acquired resistance over time. The mechanisms of resistance are complicated. The lack of established therapeutic options for patients after a failed EGFR-TKI treatment poses a great challenge to physicians in managing this group of lung cancer patients. This study evaluates the influence of EGFR-TKI retreatment following chemotherapy after failure of initial EGFR-TKI within at least 6 months on NSCLC patients. Methods： ＇i-he data of 27 patients who experienced treatment failure from their initial use of EGFR-TKI within at least 6 months were analyzed. After chemotherapy, the patients were retreated with EGFR-TKI （gefitinib 250 mg qd or erlotinib 150 mg qd）, and the tumor progression was observed. The patients were assessed for adverse events and response to therapy. Targeted tumor lesions were assessed with CT scan. Results： Of the 27 patients who received EGFR-TKI retreatment~ 1 （3.7%） patient was observed in complete response （CR）, 8 （29.6%） patients in partial response （PR）, 14 （51.9%） patients in stable disease （SD）, and 4 （14.8%） patients in progressive disease （PD）. The disease control rate （DCR） was 85.2% （95% CI： 62%-94%）. The median progression-free survival （mPFS） was 6 months （95% CI： 1-29）. Of the 13 patients who received the same EGFR-TKI, 1 patient in CR, 3 patients in PR, 8 patients in SD, and 2 patients in PD were observed. The DCRwas 84.6%, and the mPFS was 5 months. Of the 14 patients who received another EGFR-TKI, no patient in CR~ 6 patients in PR, 6 patients in SD, and 2 patients in PD were observed. The DCRwas 85.7%, and the mPFS was 9.5 months. Significant di     

吉非替尼治疗晚期复治性非小细胞肺癌41例

Objective  We observe the curative effect, median survival time, time to progression, quality of life and adverse effect of patients with advanced refractory non-small cell lung cancer (NSCLC) after gefitinib (Iressa) treatment. Methods  Forty-one patients with grade IIIb to IV NSCLC previously treated with two chemotherapy including 85.4% of patients after second line therapy were chosen. The regimen was oral intake of gefitinib 250 mg once daily until the disease progression or toxic reaction has become intolerable. The patients were required to receive tumor evaluation before the treatment, one month, two month and every three months after Iressa administration. Results  All of 41 patients were evaluable for therapeutic effect. Without complete regression being observed, partial response rate (PR), stable disease (SD) and progression of disease (PD) were 43.9% (18/41), 34.1% (14/41) and 22.1% (9/41), respectively. The overall response rate was 43.9% (18/41) and disease control rate (PR + SD) was 78% (32/41). The response rate in male was 42.1%, while it in female was 45.5% (P > 0.05). Twenty-two of them (53.7%, 22/41) were still alive with 10.1 months of MST when the follow-up ended in November 2006. TTP and MST of patients who died was 2.7 and 5.0 months, respectively. The rate of symptom improvement was 78% of all patients with 13 months of MST of PR patients. The Karnofsky enhanced 20 ± 5 after 28 days treatment without 3–4 degree of reactive toxicity. Conclusion  Iressa has significant antitumor activity in advanced NSCLC patients who have previously failed in second or third line chemotherapy. Iressa is effective and safe for patients with poor performance status.     

首次复发NSCLC患者血清CEA水平与EGFR-TKI疗效相关性分析

目的回顾性分析首次复发的晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者血清CEA表达水平和表皮生长因子受体(epidermal growth factor receptor,EGFR)基因突变及表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor tyrosine kinase inhibitor,EGFR-TKI)疗效之间的关系。方法收集2010-01-21-2014-06-30石河子大学第一附属医院治疗后首次复发并口服EGFR-TKI药物治疗的晚期NSCLC患者103例,ADx-ARMS法检测患者组织标本中EGFR 29种突变,电化学发光法检测血清CEA水平,分析血清CEA表达水平和EGFR基因突变及EGFR-TKI疗效之间的关系。结果 103例复发的晚期NSCLC患者中,EGFR总突变率为62.1%(64/103)。女性突变率显著高于男性,χ2=6.695,P=0.010。腺癌突变率高于鳞癌,χ2=4.615,P=0.032。非吸烟患者突变率显著高于吸烟患者,χ2=6.876,P=0.009。血清CEA≥5.0ng/mL时患者EGFR突变率显著高于<5.0ng/mL的患者,χ2=12.323,P<0.001。多变量Logistic分析发现,首次复发时血清CEA表达水平与EGFR基因突变正相关,P=0.001。当血清CEA<5ng/mL时,患者的疾病有效率为20.6%(7/34),疾病控制率为47.1%(16/34);血清CEA≥5ng/mL时,患者的疾病有效率为31.9%(22/69),疾病控制率为72.5%(50/69)。不同CEA水平患者经EGFR-TKI治疗后,疗效差异有统计学意义,z=-2.229,P=0.026。结论血清CEA表达水平是EGFR基因突变的独立预测因素,同时对难以获得组织的复发晚期NSCLC患者,其水平也可作为预测EGFR-TKI药物疗效的参考指标。     

EGFR在非小细胞肺癌中的表达及临床意义

目的：探讨表皮生长因子受体（EGFR）在非小细胞肺癌（NSCLC）中的表达及其与NSCLC发生、发展及预后的关系,指导非小细胞肺癌的靶向治疗。方法：回顾性分析82例NSCLC手术病例临床病理资料及随访资料,用免疫组化（EnVision法）的方法观察EGFR在非小细胞肺癌组织中的表达,对比分析20例非恶性肺组织中EGFR的表达。结果：EGFR在NSCLC中的表达率为53.66%,在非恶性肺组织中EGFR均呈阴性表达;EGFR在NSCLC中的表达与患者的性别、病理类型、TNM分期及淋巴结转移有显著统计学意义（P〈0.05）;EGFR高表达者生存期短。结论：EGFR在NSCLC中高表达;女性患者高于男性,并且与患者的病理类型、TNM分期及淋巴结转移有密切的关系,可作为判断NSCLC患者病情进展及预后的重要指标,还可以指导NSCLC患者的靶向治疗。     

A phase II trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations

Retrospective analysis has shown that activating mutations in exons 18–21 of the epidermal growth factor receptor (EGFR) gene are a predictor of response to gefitinib. We conducted a phase II trial to evaluate the efficacy and safety of gefitinib as first-line therapy for advanced non-small cell lung cancer (NSCLC) with EGFR mutations. Patients with stage IIIB or IV chemotherapy-naïve NSCLC with EGFR mutation were treated with 250 mg gefitinib daily. For mutational analysis, DNA was extracted from paraffin-embedded tissues and EGFR mutations were analysed by direct sequence of PCR products. Twenty (24%) of the 82 patients analysed had EGFR mutations (deletions in or near E746-A750, n=16; L858R, n=4). Sixteen patients were enrolled and treated with gefitinib. Twelve patients had objective response and response rate was 75% (95% CI, 48–93%). After a median follow-up of 12.7 months (range, 3.1–16.8 months), 10 patients demonstrated disease progression, with median progression-free survival of 8.9 months (95% CI, 6.7–11.1 months). The median overall survival time has not yet been reached. Most of the toxicities were mild. This study showed that gefitinib is very active and well tolerated as first-line therapy for advanced NSCLC with EGFR mutations.     

EGFR在女性非小细胞肺癌中的表达及临床意义

背景与目的：近年来女性肺癌发病率的明显增加引起人们的关注.本研究主要是以女性非小细胞肺癌为研究对象,探讨表皮生长因子受体（epidermal growth fator receptor,EGFR）在女性非小细胞肺癌（non-small cell lung cancer,NSCLC）中的表达及其与女性NSCLC发生、发展及预后的关系,指导女性非小细胞肺癌的靶向治疗.方法：回顾性分析62例女性非小细胞肺癌手术病例临床病理资料及随访资料,用免疫组化的方法检测EGFR在女性非小细胞肺癌组织中的表达,对比分析10例非恶性肺组织中EGFR的表达,用Cox模型进行生存分析.结果：EGFR在62例女性NSCLC中的表达率70.97%,在非恶性肺组织中均呈阴性表达,两者比较差异有显著性（P＜0.05）;EGFR在女性腺癌的表达高于鳞癌（P＜0.05）,尤其在细支气管肺泡癌中的表达更高（P＜0.05）;EGFR表达与女性NSCLC的TNM分期及淋巴结转移呈显著正相关（P＜0.05）;EGFR高表达的女性患者生存期短、预后差（P＜0.05）;Cox比例风险模型分析表明,患者术后生存时间与病理类型、淋巴结是否转移显著相关（P＜0.05）,腺癌、有淋巴结转移是患者独立的不良预后因素.结论：女性NSCLC中EGFR的表达与患者病理类型、TNM分期及淋巴结转移有密切的关系,EGFR在女性NSCLC中高表达,可作为判断女性NSCLC病情进展及预后的重要指标,还对NSCLC女性患者的靶向治疗的选择有一定的指导意义.     

云南地区晚期非小细胞肺癌患者的基因突变及其临床意义

目的:探讨云南地区晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者外周血中肺癌相关驱动基因突变及其与临床病理特征的关系.方法:收集2019年1月至2019年12月云南省肿瘤医院分子诊断中心检测的304例Ⅳ期NSCLC患者外周血,用二代测序(next generation sequ...     

晚期非小细胞肺癌 EGFR-TKI 获得性耐药机制

随着分子生物学的发展,晚期非小细胞肺癌的治疗由传统的化疗转向以基因分型为指导的分子靶向治疗。其中应用较多的是表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）类药物。然而EGFR-TKI 的耐药问题近年来受到越来越多的关注,其机制主要有 EGFR 基因二次突变,c-MET、人类表皮生长因子受体2（Her2）等靶基因的扩增,组织表型的改变,旁路途径的激活,p53基因的缺失,细胞信号通路负反馈的减弱以及多重机制叠加等。     

Pharmacogenomics of EGFR-targeted therapies in non-small cell lung cancer:EGFR and beyond

Commonly observed aberrations in epidermal growth factor receptor (EGFR) signaling have led to the development of EGFR-targeted therapies for various cancers, including non–small cell lung cancer (NSCL...     

EGFR-TKI治疗非小细胞肺癌研究进展

吉非替尼和厄洛替尼均为小分子量表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI),已在化疗失败的晚期非小细胞肺癌(NSCLC)解救治疗中取得疗效,但仅对特定人群发挥作用。EGFR- TKI联合化疗一线治疗NSCLC并未能提高疗效;正在进行的临床研究聚焦于优势人群EGFR-TKI一线治疗或联合化疗的研究。     

Inhibition of mitochondrial glutaminase activity reverses acquired erlotinib resistance in non-small cell lung cancer

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib has been approved based on the clinical benefit in non-small cell lung cancer (NSCLC) patients over the past decade. Unfortunately, cancer cells become resistant to this agent via various mechanisms, and this limits the improvement in patient outcomes. Thus, it is urgent to develop novel agents to overcome erlotinib resistance. Here, we propose a novel strategy to overcome acquired erlotinib resistance in NSCLC by inhibiting glutaminase activity. Compound 968, an inhibitor of the glutaminase C (GAC), when combined with erlotinib potently inhibited the cell proliferation of erlotinib-resistant NSCLC cells HCC827ER and NCI-H1975. The combination of compound 968 and erlotinib not only decreased GAC and EGFR protein expression but also inhibited GAC activity in HCC827ER cells. The growth of erlotinib-resistant cells was glutamine-dependent as proved by GAC gene knocked down and rescue experiment. More importantly, compound 968 combined with erlotinib down-regulated the glutamine and glycolysis metabolism in erlotinib-resistant cells. Taken together, our study provides a valuable approach to overcome acquired erlotinib resistance by blocking glutamine metabolism and suggests that combination of EGFR-TKI and GAC inhibitor maybe a potential treatment strategy for acquired erlotinib-resistant NSCLC.     

EGFR-TKI治疗非小细胞肺癌研究进展

吉非替尼和厄洛替尼均为小分子量表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）,已在化疗失败的晚期非小细胞肺癌（NSCLC）解救治疗中取得疗效,但仅对特定人群发挥作用。EGF冀。TKI联合化疗一线治疗NSCLC并未能提高疗效;正在进行的临床研究聚焦于优势人群EGFR-TKI一线治疗或联合化疗的研究。     

表皮生长因子受体酪氨酸激酶抑制剂与非小细胞肺癌的治疗

 表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）是一类高效低毒的抗肿瘤分子靶向药物,因其独特的疗效和良好的耐受性在非小细胞肺癌（NSCLC）治疗中成为研究的热点,在NSCLC的一线、二线或三线的辅助治疗中均有一定地位。随着研究的深入细化,EGFR TKI的适应证不断扩大,术前新辅助治疗可能成为一种新的治疗模式。