Efficacy of S-1 in non-small cell lung cancer

Introduction: S-1 is an oral fluoropyrimidine derivative, including three pharmacological compounds: tegafur, gimeracil and oteracil, in a molar ratio of 1: 0.4: 1.

Areas covered: This review addresses the clinical evidence of S-1 in NSCLC in various clinical settings. Currently, S-1 for NSCLC is approved only in Japan. Prospective studies of S-1 as front-line and second-line chemotherapy with or without other agents and concurrent chemoradiotherapy are mainly reviewed. Only two Phase III clinical trials were published or presented for advanced NSCLC. S-1 and cisplatin is an active first-line chemotherapy regimen for advanced NSCLC and S-1 and carboplatin is noninferior to a carboplatin and paclitaexel regimen. The combination of S-1 and a platinum agent is active against NSCLC, regardless of tumor histology.

Expert opinion: It is becoming possible to design effective regimens with S-1 against NSCLC in various clinical settings considering the ethnic differences in pharmacokinetics and a greater understanding of the underlying molecular pathways or biomarkers of NSCLC. Further Phase III studies with S-1 for both early and advanced NSCLC are warranted worldwide.     

Entrectinib: a potent new TRK,ROS1, and ALK inhibitor

Introduction: Receptor tyrosine kinases (RTKs) and their signaling pathways, control normal cellular processes; however, their deregulation play important roles in malignant transformation. In advanced non-small cell lung cancer (NSCLC), the recognition of oncogenic activation of specific RTKs, has led to the development of molecularly targeted agents that only benefit roughly 20% of patients. Entrectinib is a pan-TRK, ROS1 and ALK inhibitor that has shown potent anti-neoplastic activity and tolerability in various neoplastic conditions, particularly NSCLC.

Areas covered: This review outlines the pharmacokinetics, pharmacodynamics, mechanism of action, safety, tolerability, pre-clinical studies and clinical trials of entrectinib, a promising novel agent for the treatment of advanced solid tumors with molecular alterations of Trk-A, B and C, ROS1 or ALK.

Expert opinion: Among the several experimental drugs under clinical development, entrectinib is emerging as an innovative and promising targeted agent. The encouraging antitumor activity reported in the Phase 1 studies, together with the acceptable toxicity profile, suggest that entrectinib, thanks to its peculiar mechanism of action, could play an important role in the treatment-strategies of multiple TRK-A, B, C, ROS1, and ALK- dependent solid tumors, including NSCLC and colorectal cancer. That being said, further evidence for its clinical use is still needed.     

外周血LFA-1和ICAM-1在非小细胞肺癌中的临床意义及表达

目的：探讨非小细胞肺癌血清中LFA-1和ICAM-1的表达在肿瘤侵袭转移过程中的作用机制。方法：采用双抗体夹心ABC-ELISA法测定。结果：（1）非小细胞肺癌患者血清中LFA—1和ICAM-1的含量明显高于对照组;差异具有显著性（P〈0．01）;（2）非小细胞肺癌患者LFA-1和ICAM-1间存在正相关性（P〈0．05）。（3）肺癌的I＋N期与I＋Ⅱ期相比血清LFA-1、ICAM-1均有显著差异（P〈0．05）。（4）有淋巴结转移者血清LFA-1和1CAM-1含量较无淋巴结转移者增高,差异显著（P〈0．05）。结论：LFA-1 ICAM-1可能是反映肺癌侵袭转移潜能的一个有效生物学指标。     

Panx1在非小细胞肺癌组织中的表达及临床意义

目的 研究Panx1（Pannexin1）在人非小细胞肺癌（NSCLC）中的表达情况,并分析其临床意义。方法 应用实时荧光定量PCR法检测25例非小细胞肺癌组织及配对的癌旁组织中Panx1 mRNA的表达。应用免疫组织化学染色法检测30例非小细胞肺癌组织、配对的癌旁组织及10例正常肺组织中Panx1蛋白的表达,分析其表达与临床病理特征的关系。结果 NSCLC中Panx1 mRNA和Panx1蛋白的表达水平均高于癌旁组织,差异有统计学意义（P＜0.05）。不同年龄、性别、胸膜侵袭情况、病理分级分组的NSCLC患者组织中Panx1蛋白阳性表达率比较差异无统计学意义（P＞0.05）,TNM临床分期Ⅲ~Ⅳ期组的Panx1阳性表达率高于Ⅰ~Ⅱ期组,有淋巴结转移组的Panx1阳性表达率高于无淋巴结转移组,差异均有统计学意义（P＜0.05）。结论 Panx1在NSCLC组织中显著高表达,而在癌旁组织中低表达,提示Panx1可能在NSCLC的发生、发展及转移侵袭中起重要作用。     

TTF-1在小细胞肺癌与非小细胞肺癌中的表达及鉴别诊断意义的Meta分析

目的探讨甲状腺转录因子-1(TTF-1)在小细胞肺癌(small-cell lung cancer,SCLC)与非小细胞肺癌(non-small cell lung cancer,NSCLC)中的表达及鉴别诊断意义。方法检索PubMed、ISI WebOf Knowledge平台、中国学术期刊全文数据库、万方数据库等,收集1996～2012年国内外公开发表的论文,均为TTF-1在SCLC及NSCLC组织表达的临床研究;对文献进行异质性检验,以SCLC组及NSCLC组比值比(OR值)为效应指标,应用Meta分析软件(RevMan4.2.10)对各研究原始数据进行统计分析,计算合并OR值及95%可信区间(95%CI),同时绘制Meta分析森林图和倒漏斗图。结果共有7篇研究纳入系统评价,共计SCLC患者115例,NSCLC患者664例;Meta分析结果合并OR值为3.22,95%CI为2.02～5.13。结论 TTF-1在SCLC中的阳性表达率明显高于NSCLC,差异有统计学意义(P<0.05);TTF-1高表达可能在SCLC的发生、发展中起重要作用,这对于SCLC与NSCLC的鉴别诊断具有重要参考意义。     

Long non-coding RNA DDX11-AS1 promotes non-small cell lung cancer development via regulating PI3K/AKT signalling

Non-small cell lung cancer (NSCLC) has been considered to be the most common category of lung cancer, comprising approximately 80% of lung cancers. Long non-coding RNAs (lncRNAs) were diffusely documented to modulate carcinogenesis or progression of tumours. However, the role of DDX11-AS1 was still unclear in NSCLC. Bioinformatics analysis and experimental assays including hematoxylin and eosin (H&E) staining, RT-qPCR, colony formation, CCK-8, flow cytometry, western blot and xenograft assays were applied to investigate the biological role and molecular mechanism of DDX11-AS1 in NSCLC. The level of lncRNA DDX11-AS1 was up-regulated in NSCLC tumour tissues and cells. In function aspect, knockdown of DDX11-AS1 caused an apparent inhibitive effect on cell proliferation in vitro and in vivo. DDX11-AS1 inhibition promoted cell apoptosis in vitro. In mechanism, the protein level of phosphorylated AKT was reduced by DDX11-AS1 inhibition but increased by DDX11-AS1 overexpression. These results indicated that DDX11-AS1 exacerbated NSCLC progression via activating PI3K/AKT signalling pathway. All in all, DDX11-AS1 promotes NSCLC development via regulating PI3K/AKT signalling.     

PD0325901, an ERK inhibitor,enhances the efficacy of PD-1 inhibitor in non-small cell lung carcinoma

ERK pathway regulated the programmed death ligand-1 (PD-L1) expression which was linked to the response of programmed death-1 (PD-1)/PD-L1 blockade therapy. So it is deducible that ERK inhibitor could enhance the efficacy of PD-1 inhibitor in cancer immunotherapy. In this study, PD0325901, an oral potent ERK inhibitor, strongly enhanced the efficacy of PD-1 antibody in vitro and in vivo models in non-small cell lung carcinoma (NSCLC) cells. Mechanistically, PD0325901 or shRNA-ERK1/2 significantly downregulated the PD-L1 expression in NSCLC cells and increased the CD3⁺ T cells infiltration and functions in tumor tissue. There was a positive correlation between the p-ERK1/2 expression and PD-L1 expression in patients with NSCLC. And the patients with low p-ERK1/2 expression were observed a high response rate of PD-1/PD-L1 blockage therapy. Our results demonstrate that PD0325901, an ERK inhibitor, can enhance the efficacy of PD-1 blockage against NSCLC in vitro and in vivo models. And the combination of ERK inhibitor such as PD0325901 and PD-1/PD-L1 blockage is a promising regimen and encouraged to be further confirmed in the treatment of patients with NSCLC.     

肝再生磷酸酶-3在非小细胞肺癌的表达及意义

目的研究肝再生磷酸酶-3(PRL-3)在非小细胞肺癌(NSCLC)的表达及意义。方法采用免疫组化法检测25例对照组和51例NSCLC患者PRL-3表达水平并进行分析比较。结果 PRL-3在对照组、肺癌组的阳性表达率分别为12.00%和74.51%(P<0.05);PRL-3的表达与非小细胞肺癌有无淋巴结转移及临床分期有关(P<0.05),与年龄、性别、病理类型无关(P>0.05)。结论 PRL-3表达与非小细胞肺癌的发生发展有一定的关系,PRL-3检测可作为判定非小细胞肺癌浸润及转移程度的一个生物学指标。     

程序性死亡配体-1在人非小细胞肺癌组织中的表达及临床意义

目的：探讨程序性死亡配体‐1（PD‐L1）在人非小细胞肺癌（NSCLC）组织中的表达及临床意义。方法采用Western blot和免疫组织化学染色法检测41例NSCLC患者的肺癌组织、癌旁组织、正常肺组织和15例肺部良性病变患者的正常肺组织中的 PD‐L1表达,分析NSCLC患者PD‐L1表达的影响因素。结果 NSCLC患者肺癌组织中 PD‐L1阳性表达率为80.49％（33／41）,肺良性病变患者正常肺组织中几乎无PD‐L1表达。NSCLC患者肺癌组织中 PD‐L1表达高于癌旁组织及正常肺组织（P＜0．05）。PD‐L1的表达与肿瘤患者分期、淋巴结转移和远处转移相关（P＜0．05）,而与肿瘤病理分型、患者年龄、性别、吸烟史及肿瘤大小等无关（ P＞0．05）。结论 PD‐L1在NSCLC组织中显著高表达,在NSCLC进展中发挥重要作用,可能成为NSCLC预后的判断指标及免疫治疗的新靶点。     

长链非编码RNA TPT1-AS1在非小细胞肺癌中的表达及临床意义

目的 分析长链非编码RNA(lncRNA)TPT1-AS1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 收集2014年7月至2016年9月陕西省核工业二一五医院非小细胞肺癌标本及癌旁组织各100例,采用实时荧光定量PCR(qRT-PCR)检测非小细胞肺癌标本、癌旁组织中lncRNA TPT1-AS1表达情况,分...     

Cofilin1及其Ser3位点磷酸化与老年非小细胞肺癌患者放疗敏感性的相关性研究

目的 探讨Cofilin1及其Ser3位点磷酸化水平与老年非小细胞肺癌（NSCLC）患者放疗敏感性的相关性。方法 选取2013年6月—2015年4月于我院行手术切除、经病理确诊并接受术后放疗的老年NSCLC患者102例,根据疗效分为放疗敏感组（55例）和放疗抵抗组（47例）,检测Cofilin1及其Ser3位点磷酸化蛋白Cofilin1（phospho S3）的表达,并记录患者的生存时间和生存率。结果 放疗抵抗组Cofilin1阳性表达组织的TNM分期和淋巴结转移率均显著升高,而Cofilin1（phospho S3）阳性表达组织显著降低（P<0.05）。放疗抵抗组的Cofilin1阳性表达率显著高于放疗敏感组,而放疗敏感组的Cofilin1（phospho S3）阳性表达率显著高于放疗抵抗组（P<0.05）。淋巴结转移、Cofilin1高表达、Cofilin1（phospho S3）低表达是放疗抵抗的独立预测因素（P<0.05）。放疗敏感组、Cofilin1阴性患者、Cofilin1（phospho S3）阳性患者的无进展生存时间（PFS）较长、5年生存率较高（P<0.05）;放疗敏感组中,Cofilin1阴性和Cofilin1（phospho S3）阳性患者PFS最长、5年生存率最高（P<0.05）;放疗抵抗组中,Cofilin1阳性和Cofilin1（phospho S3）阴性患者PFS最短、5年生存率最低（P<0.05）。结论 老年NSCLC患者的放疗敏感性与Cofilin1表达呈明显负相关,与Cofilin1的Ser3位点磷酸化水平呈显著正相关。Cofilin1及其Ser3位点磷酸化是放疗敏感性的独立预测因素,对老年NSCLC患者的预后评估具有重要意义。     

ERCCI与BRCA1在非小细胞肺癌及癌旁组织中的表达及临床意义

目的 探讨DNA修复基因ERCCI与BRCA1在非小细胞肺癌(NSCLC)中的表达及临床意义.方法 应用免疫组织化学方法 检测32例肺癌,24例癌旁组织ERCCI与BRCA1的表达.结果 NSCLC中ERCCI与BRCA1在癌旁组织内表达高于癌组织,且差异具有统计学意义(P<0.05);BRCA1在淋巴结有无转移之间表达差异具有统计学意义(P<0.05).结论 NSCLC中,ERCCI与BRCA1在癌旁组织的表达高于癌组织,BRCA1可作为判断预后的一项指标.     

氧化还原因子与非小细胞肺癌的相关性研究

目的探讨氧化还原因子(Ref-1)在非小细胞肺癌(NSCLC)组织中的表达与预后之间的关系。方法应用免疫组织化学Envison法检测Ref-1蛋白在88例NSCLC和20例正常肺组织中的表达,并与临床及病理特征进行比较分析。结果Ref-1在NSCLC组织中阳性表达率为68%,而在正常肺组织为5%,两者差异有统计学意义(P<0.01)。Ref-1蛋白表达与性别、年龄、吸烟、肿瘤病理类型等临床参数无关(P>0.05),而与分化、淋巴结转移、临床分期明显相关(P<0.05)。结论Ref-1蛋白在肺癌组织中表达上调,提示其对NSCLC的发生发展起重要作用,肺癌组织中Ref-1过表达提示患者预后不良。     

RRM1和ERCC1基因外周血中表达水平与吉西他滨联合铂类治疗晚期非小细胞肺癌疗效的相关性研究

目的:探讨外周血中DNA修复基因RRM1(核苷酸还原酶,ribonucleotide reductase M1)和ERCC1(切除修复交叉互补组基因1,excision repair cross-complementation 1)的表达水平与吉西他滨联合铂类治疗非小细胞肺癌(Nonsmall-cell lung cancer,NSCLC)疗效的相关性.方法:SYBR荧光实时定量PCR检测NSCLC组织和外周血中RRM1和ERCC1 mRNA表达水平.分类变量之间进行x2检验,连续性变量之间进行Spearman等级相关性分析;总体生存率的比较采用Kaplan-Meier生存曲线和log-rank检验.结果:本研究中,34例晚期NSCLC患者外周血RRM1和ERCC1 mRNA表达水平进行了有效地检测,22例病例同时进行了肿瘤组织和外周血的基因检测.RRM1 mRNA的相对表达量在外周血和肿瘤组织中存在线性相关性(R2=0.045,P=0.048),而ERCC1在两者之间无线性相关(R2=0.016,P=0.251).RRM1低表达组的生存期(16.0月)明显长于高表达组(12.5月)(Log-rank 3.980,P=0.046).而ERCC1的表达在两组间无统计学意义(P＞0.05).结论:研究表明,在入组的NSCLC患者中,外周血中RRM1低表达组的生存期明显长于高表达组,对化疗反应的有效率更高,其结果有助于筛选出接受吉西他滨联合铂类化疗方案的患者.     

EphA2和KAI-1在非小细胞肺癌中的表达及意义

目的：进一步从分子水平研究肺癌发生发展的机制。方法：应用免疫组化SP法检测45例非小细胞肺癌（NSCLC）、30例癌旁组织中EphA2,KAI和FAK蛋白的表达。结果：（1）NSCLC中EphA2和FAK高表达,KAI-1低表达,与正常肺组织比较P〈0.01,有显著差异性。KAI-1,FAK与肺癌的分化程度,临床分期,淋巴结转移有密切相关性,EphA2只与临床分期,淋巴结转移相关。（2）NSCLC中EphA2与FAK呈正相关,KAI-1与FAK负相关,P均〈0.05,EphA2与KAI-1无明显相关性（P〉0.05）。结论：EphA2,KAI1和FAK可联合作为指标,用于评价肺癌的发展和预后。     

MUC1蛋白在非小细胞肺癌早期诊断中的临床价值

摘要：目的 探讨黏蛋白1（MUC1）在不同类型非小细胞肺癌（NSCLC）患者血清和癌组织中的表达情况,并分析 其在NSCLC患者临床早期诊断及治疗中的预测价值。方法 收集2017年12月—2018年12月宁夏医科大学总医院 收治的 34 例肺鳞癌、65 例肺腺癌和 20 例非肺癌患者外周血及肺组织。采用酶联免疫吸附法（ELISA）检测血清 MUC1蛋白表达。所收取肺组织标本均经HE染色证实符合病理要求后,采用免疫组织化学染色法检测MUC1蛋白 表达。采用受试者工作特征（ROC）曲线分析血清中MUC1蛋白预测不同类型NSCLC患者的临床价值。结果 肺鳞 癌和肺腺癌患者血清及癌组织中MUC1蛋白表达水平均高于非肺癌组（P＜0.05）。血清MUC1蛋白诊断肺鳞癌的最 佳临界值为33.23 U/mL,其诊断敏感度为52.94%,特异度为100%;肺鳞癌患者血清及癌组织中的MUC1蛋白阳性表 达率与病理分化程度、TNM分期、年龄、性别均无关（P＞0.05）;血清MUC1蛋白诊断肺腺癌的最佳临界值为31.31 U/ mL,其诊断敏感度为61.54%,特异度为95%;肺腺癌组中-低组织分化、TNM分期Ⅲ~Ⅳ期组患者血清及癌组织MUC1 蛋白阳性表达率分别高于高组织分化、TNM分期Ⅰ~Ⅱ期组（P＜0.05）。结论 NSCLC患者中MUC1蛋白呈高表达, 其对肺腺癌临床早期诊断及治疗可能有预测意义,对肺鳞癌无明显预测意义。     

Pharmacogenetics of platinum-based chemotherapy in non-small cell lung cancer: predictive validity of polymorphisms of ERCC1

Introduction: The efficacy of platinum-based chemotherapy for patients with non-small cell lung cancer (NSCLC) is limited by chemoresistance. Platinum drugs damage DNA by introducing intrastrand and interstrand crosslinks which result in cell death. Excision repair cross-complementing 1 (ERCC1) is a member of the nucleotide excision repair (NER) pathway which erases such defects. Single nucleotide polymorphisms (SNPs) in ERCC1 impair this activity and have been suggested to predict the response to chemotherapy.

Area covered: Among the polymorphisms of proteins involved in uptake, metabolism, cytotoxicity and efflux of platinum drugs, codon 118 C/T and C8092A in ERCC1 are the best characterized SNPs studied for their predictive power. Here, the divergent results for studies of these markers in NSCLC are summarized and the reasons for this contradictory data discussed.

Expert opinion: Cytotoxicity of platinum compounds comprise complex cellular processes for which DNA repair may not constitute the rate limiting step. These drugs are administered as doublets to histologically diverse patients and, furthermore, the NER pathway in ERCC1 wildtype cohorts may be still impaired by the chemotherapeutics applied. At present, assessment of a limited number of polymorphism in DNA repair proteins is not reliably associated with response to treatment in NSCLC patients.     

Monosaccharide digitoxin derivative sensitize human non-small cell lung cancer cells to anoikis through Mcl-1 proteasomal degradation

Advanced stage cancers acquire anoikis resistance which provides metastatic potential to invade and form tumors at distant sites. Suppression of anoikis resistance by novel molecular therapies would greatly benefit treatment strategies for metastatic cancers. Recently, digitoxin and several of its novel synthetic derivatives, such as α-l-rhamnose monosaccharide derivative (D6-MA), have been synthesized and studied for their profound anticancer activity in various cancer cell lines. In this study, we investigated the anoikis sensitizing effect of D6-MA compared with digitoxin to identify their anti-metastatic mechanism of action. D6-MA sensitized NSCLC H460 cells to detachment-induced apoptosis with significantly greater cytotoxicity (IC50 = 11.9 nM) than digitoxin (IC50 = 90.7 nM) by activating caspase-9. Screening of the Bcl-2 protein family revealed that degradation of anti-apoptotic Mcl-1 protein is a favorable target. Mcl-1 over-expression and knockdown studies in D6-MA and digitoxin exposed cells resulted in rescue and enhancement, respectively, indicating a facilitative role for decreased Mcl-1 expression in NSCLC anoikis. Transfection with mutant Mcl-1S159 attenuated detachment-induced cell death and correlated with a remaining of Mcl-1 level. Furthermore, D6-MA suppressed Mcl-1 expression via ubiquitin proteasomal degradation that is dependent on activation of glycogen synthase kinase (GSK)-3β signaling. In addition, D6-MA also targeted Mcl-1 degradation causing an increased anoikis in A549 lung cancer cells. Anoikis sensitizing effect on normal small airway epithelial cells was not observed indicating the specificity of D6-MA and digitoxin for NSCLC. These results identify a novel cardiac glycoside (CG) sensitizing anoikis mechanism and provide a promising anti-metastatic target for lung cancer therapy.