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。     

非小细胞肺癌获得性表皮生长因子受体酪氨酸激酶抑制剂耐药治疗疗效观察

目的探讨非小细胞肺癌(NSCLC)患者获得性表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)耐药后后续化疗联合沙利度胺和化疗序贯EGFR-TKIs治疗的疗效。方法选取2016年1月至2017年2月间安徽省芜湖市第二人民医院收治的经EGFR-TKIs治疗起效并出现获得性耐药的41例NSCLC患者,采用随机数字生成法分为A组和B组。A组21例患者采用多西他赛、培美曲赛和顺铂化疗,联合沙利度胺口服治疗; B组20例患者采用多西他赛、培美曲赛和顺铂化疗,序贯EGFR-TKIs治疗。比较两组患者的近期疗效、中位无进展生存时间(PFS)及不良反应。结果两组患者近期疗效比较,差异无统计学意义(P> 0. 05)。两组患者中位PFS比较,差异无统计学意义(P> 0. 05)。A组患者便秘发生率高于B组,恶心、呕吐发生率低于B组,组间差异均有统计学意义(均P <0. 05)。结论常规化疗联合沙利度胺和常规化疗序贯EGFR-TKIs治疗均可作为获得性EGFR-TKIs耐药NSCLC晚期患者的后续治疗方案,临床可根据实际情况选用。     

环氧合酶-2和表皮生长因子受体在非小细胞肺癌的表达及意义

目的 :探讨环氧合酶 2 (COX 2 )和表皮生长因子受体 (EGFR)在非小细胞肺癌 (NSCLC)中的表达与意义。方法 :应用免疫组织化学染色EnVision法检测 6 0例根治术后NSCLC肿瘤组织中COX 2和EGFR的表达。应用 χ2 检验和COX回归分析等比较COX 2和EGFR在不同分化级别的肺鳞癌和腺癌中表达上的差异及其与术后患者生存期之间的关系。结果 :77%肺腺癌表达COX 2 ,表达率明显高于肺鳞癌的 37% (χ2 =9.774 ,P <0 .0 1) ;NSCLC中COX 2和EGFR的表达与患者年龄、性别、肿瘤分化级别、原发灶大小、淋巴结转移范围和 p TNM分期等因素无关。COX 2表达“ ”和“ ”和EGFR表达“ ”与“ ”患者的中位生存期分别为 30个月和 16个月与 34个月和 15个月 ,均明显低于各自不表达患者的 4 5个月 (P <0 .0 5 )。COX多因素回归分析示COX 2表达和p TNM分期是影响该组NSCLC患者预后的两个独立因素。在肺鳞癌 ,EGFR也与预后不良有关。 结论 :COX 2和EGFR在NSCLC有表达 ,表达者预后较差。     

酪氨酸激酶抑制剂在非小细胞肺癌中的耐药机制

EGFR-TKIs在EGFR突变型非小细胞肺癌治疗中是非常有效的。然而在非小细胞肺癌EGFR突变患者中约有20%天然耐药,即使治疗有效,在10~16月左右会产生继发耐药。迄今为止,研究发现可能的继发性耐药机制包括EGFR二次突变、旁路激活、下游信号激活、小细胞转化及上皮-间质转化（EMT）等。近期,有研究发现BIM基因与TKI耐药相关。本文就有关耐药机制的近期研究进展作一综述。     

EGFR和C-erbB2在非小细胞肺癌中的表达及研究前景

肺癌的发生和发展是一个多因素多阶段的过程,表现为癌基因、抑癌基因、肿瘤转移相关基因的点突变、扩增、异位和缺失,以及某些抗原分子的异常表达.表皮生长因子受体(EGFR)和C-erbB-2癌基因在非小细胞肺癌中过表达并与肿瘤的生长转移及患者的预后密切相关,但在小细胞肺癌中未发现过表达.本文综述了EGFR和C-erbB2的结构、功能、同源性及在正常组织中的分布,重点讨论了EGFR和C-erbB2在非小细胞肺癌(NSCLC)发生发展中的作用及在NSCLC的诊断、治疗、预后方面的应用前景.     

外泌体非编码RNA在非小细胞肺癌获得性耐药中的研究进展

非小细胞肺癌(non-small cell lung cancer,NSCLC)是肺癌中最常见的类型,对化疗及靶向药物的获得性耐药严重影响NSCLC患者的生存期,NSCLC获得性耐药机制复杂,确切机制仍不清楚.肿瘤来源或与肿瘤相关的外泌体是参与调控NSCLC获得性耐药的重要机制,可以通过传递核酸、蛋白质等赋予敏感细胞耐...     

中药延缓非小细胞肺癌表皮生长因子受体-酪氨酸激酶抑制剂耐药机制的研究进展

近年来,表皮生长因子受体-酪氨酸激酶抑制剂（EGFR-TKI）为EGFR突变阳性的非小细胞肺癌（NSCLC）患者带来了显著的疗效,但其不可避免的耐药性是临床治疗面临的最大难题。中医药作为肿瘤综合治疗的重要组成部分,在延缓EGFR-TKI耐药方面具有显著优势。本文从抑制EGFR下游通路异常激活、抑制EGFR旁路代偿性激活、抑制上皮-间充质转化、表观遗传调控等方面综述了中医药延缓NSCLC EGFR-TKI耐药机制的研究进展,并总结了目前中药延缓EGFR-TKI耐药的实验研究的不足之处,以期为临床制订中医药联合EGFR-TKI治疗NSCLC的策略和方案提供有益的参考。     

免疫检查点抑制剂治疗非小细胞肺癌耐药机制研究进展

免疫是治疗晚期非小细胞肺癌（non-small cell lung cancer,NSCLC）的治疗手段之一,但由于治疗期间的原发性和获得性耐药性,很大一部分患者无法从中受益。本文总结了针对程序性死亡受体1(programmed cell death protein 1,PD-1)/程序性死亡配体1(programmed cell death ligand 1,PD-L1)的免疫检查点抑制剂在NSCLC治疗中产生耐药性的关键机制最新研究,原发性耐药机制包括PD-L1表达异常及突变、T细胞本身的异常免疫和RAS、BRAF等信号通路因素导致免疫进化等,获得性耐药机制包括TIM-3、B7-H7、VISTA、LAG-3、CTLA-4、Siglec-15、TIGIT、BTLA等代偿性免疫检查点上调,以及记忆T细胞分化失败和肿瘤的免疫编辑等。我们还讨论了对PD-1/PD-L1阻断有效的条件及PD-1/PD-L1免疫治疗的抗肿瘤活性增强的策略,为提高免疫检查点抑制剂的临床疗效提供参考。     

检查点抑制剂在非小细胞肺癌中的研究进展

近年来,非小细胞肺癌(non small cell lung cancer,NSCLC)在手术、放疗、化疗等方面均取得了很大进展,但NSCLC患者5年生存率仍只有15%,因此探索NSCLC新的治疗模式尤为重要。免疫治疗以其低毒、高效等特点成为当前肿瘤治疗的重要手段。检查点抑制剂作为新型抗肿瘤免疫治疗药物,通过阻断T细胞的负性信号传递使其大量活化增值,增强机体的抗肿瘤免疫功能,显现出了良好的抗瘤效果。目前,细胞毒性T淋巴细胞相关抗原-4(cytotoxic T lymphocyte associated antigen 4,CTLA-4)、程序性细胞死亡蛋白1(programmed death-1,PD-1)及其受体PD-L1、淋巴细胞活化基因-3分子(lymphocyte activation gene-3,LAG-3,CD223)和T细胞免疫球蛋白3(T-cell immunoglobulin and mucin-domain-containing molecule 3,TIM-3)等分子的抑制剂均在NSCLC中开展了广泛的研究。在治疗NSCLC的临床试验中,检查点抑制剂Ipilimumab、Nivoluma等取得了一定的成功,前景值得期待。     

非小细胞肺癌表皮生长因子受体酪氨酸酶激酶抑制剂的耐药机制及对策

0引言表皮生长因子受体(epidermal growth factor receptor,EGFR),即ERBB1,位于人体7号染色体短臂7p12-14区,由28个外显子组成,属于ERBB/HER超家族,具有酪氨酸激酶活性,包括1个胞外配体结合区、跨膜区和1个胞内区。EGFR与配体结合后形成同源或异源二聚体,引起构象变     

Advances in the management of acquired resistance to EGFR-TKI in non-small cell lung cancer

Drugs that specifically target the tyrosine kinase domain of epidermal growth factor receptor(EGFR), such as erlotinib or gefitinib, have exhibited striking efficacy in non-small cell lung cancer(NSCLC) patients harboring activating EGFR mutations. However, acquired resistance inevitably develops and remains a serious barrier for the successful management of patients with this disease. Multiple mechanisms are reportedly involved in the process of acquired resistance, which provide new insights into the management of EGFRtyrosine kinase inhibitor(EGFR-TKI) resistance. Here, we provide an overview of the emerging treatment approaches for patients with EGFR-TKI resistance.     

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。      

Beclin1在非小细胞肺癌的表达及其与EGFR突变的关系

目的:观察Beclin1在非小细胞肺癌(non-small cell lung cancer,NSCLC)中的表达情况,探讨其与EGFR突变的相关性.方法:分别采用DNA直接测序法、免疫组化法检测42例NSCLC患者EGFR突变情况及Beclin1表达情况,分析二者之间关系及临床意义.结果:与癌旁组织比较,NSCLC组织中Beclin1高表达(71.4％ vs 30.9％,P＜0.01),Beclin1的表达与吸烟史、病理类型有关(P =0.005,P=0.025).EGFR突变14例,其中高表达Beclin1 11例,低表达Beclin1 2例,突变率为57.9％(11/19) vs 16.7％(2/12),Beclin1的表达与EGFR突变具有显著正相关性(r=0.416,P=0.009).结论:NSCLC患者EGFR突变与Beclin1的表达具有正相关性,Beclin1表达情况在一定程度上有助于判断NSCLC的EGFR突变状况,可能为判断EGFR突变提供有意义的线索.     

MiR-21 overexpression is associated with acquired resistance of EGFR-TKI in non-small cell lung cancer

Background and purpose

With the increasing use of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) in patients with advanced non-small cell lung cancer (NSCLC), its acquired resistance has become a major clinical problem. Recent studies revealed that miR-21 was involved into the resistance of cytotoxic agents. The aim of this study was to investigate its role in the acquired resistance of NSCLC to EGFR-TKI.

Methods

EGFR-TKI-sensitive human lung adenocarcinoma cell line PC9 and the acquired resistant cell line, PC9R, were used. Lentiviral vectors were used to infect PC9 or PC9R to regulate the miR-21 expression. The expression of targeted proteins PTEN and PDCD4 was controlled by RNA interference. MicroRNA array, RT-PCR and TaqMan MicroRNA Assays were used to detect miR-21 expression. The MTT and Annexin V assays were used to determine proliferation and apoptosis. Western Blot and immunohistochemistry were used to analyze target protein expression (PTEN, PDCD4, Akt, p-Akt). We also constructed PC9R xenograft tumor model to observe the relationship between miR-21 and EGFR-TKI resistance in vivo and validated it in the clinical serum specimens of NSCLC patients treated with EGFR-TKI.

Result

MiR-21 was overexpressed in the EGFR-TKI resistant cell line PC9R relative to PC9. The level of miR-21 was reversely correlated with the expression of PTEN and PDCD4 and positive correlated with PI3K/Akt pathway. Inhibiting miR-21 with lentivirus vector induces apoptosis in PC9R cell line and inhibiting miR-21with ASO suppressed tumor growth in nude mice treated with EGFR-TKI. Furthermore, serum miR-21 expression in NSCLC patients treated with EGFR-TKI was significantly higher at the time of acquiring resistance than at baseline (p < 0.01).

Conclusion

miR-21 is involved in acquired resistance of EGFR-TKI in NSCLC, which is mediated by down-regulating PTEN and PDCD4 and activating PI3K/Akt pathway.     

非小细胞肺癌中基质金属蛋白酶-13表达及与预后的关系研究

Objective: To investigate the expression of MMP-13 in non-small cell lung cancer (NSCLC), so as to analyze its correlation with prognosis of NSCLC. Methods: MMP-13 expression was detected in 99 NSCLC tissues and 32 normal lung tissues by immunohistochemical method. Results: (1) Expression of MMP-13 (51.5%, 51/99) in cancer tissues was significantly higher than that in normal tissues 0% (P ＜ 0.05). Expression level of MMP-13 was significantly related to lymph node metastasis and clinical stage (P＜0.01). (2) Kaplan-Meier analysis showed that expression level of MMP-13 was closely correlate with the prognosis of NSCLC. Multivariate Cox model analysis suggested that the survival time was significantly related to clinical stage and the expression of MMP-13. Conclusion: MMP-13 is an independent factor that affect prognosis.     

Expression of MMP-13 and its correlation with prognosis in non-small cell-lung cancer

Objective： To investigate the expression of MMP-13 in non-small cell lung cancer （NSCLC）, so as to analyze its correlation with prognosis of NSCLC. Methods： MMP-13 expression was detected in 99 NSCLC tissues and 32 normal lung tissues by immunohistochemical method. Results： （1） Expression of MMP-13 （51.5%, 51/99） in cancer tissues was significantly higher than that in normal tissues 0% （P 〈 0.05）. Expression level of MMP-13 was significantly related to lymph node metastasis and clinical stage （P 〈 0.01）. （2） Kaplan-Meier analysis showed that expression level of MMP-13 was closely cor- relate with the prognosis of NSCLC. Multivariate Cox model analysis suggested that the survival time was significantly related to clinical stage and the expression of MMP-13. Conclusion： MMP-13 is an independent factor that affect prognosis.     

早期非小细胞肺癌预后相关因素分析

早期非小细胞肺癌患者首选手术治疗后，仍有部分出现了局部复发和／或远处转移。筛选出预后差的患者辅以综合治疗显得尤为重要。本文分析了近年来研究的一些早期非小细胞肺癌的预后因素。     

非小细胞肺癌中miRNA-141的表达及临床意义

目的:探讨miRNA-141在非小细胞肺癌中的表达及其与临床病理特征的关系。方法:采用real time-PCR法对54例非小细胞患者,肺癌组织及正常肺组织的miRNA-141表达水平进行定量分析,结果由2-△△CT处理,并分析与临床病理资料的关系。结果:在NSCLC患者肿瘤组织中miRNA-141表达水平明显升高,其表达与临床分期、病理类型显著相关(P<0.05)。而在不同年龄、性别、肿瘤大小、吸烟史患者间差异无统计学意义(P>0.05)。结论:MiRNA-141高表达与非小细胞肺癌的临床分期、病理分型密切相关,miRNA-141有可能作为非小细胞肺癌的重要肿瘤标志物之一。