IGF信号通路关键蛋白IGF1、IGF1R和AKT在原发性肺腺癌中的表达及意义

目的检测IGF信号通路关键蛋白IGF1，IGF1R和AKT在原发性肺腺癌中的表达，探讨其与临床病理学特征和生存时间的关系。方法采用免疫组化方法和免疫印迹技术检测IGF1，IGF1R和AKT在31例原发性肺腺癌及12例良性肺病变组织中的表达。结果IGF1、IGF1R和AKT在肺腺癌中的表达率分别为41．9％（13／31）、67．7％（21／31）和51．6％（16／31），显著高于良性肺组织（P值分别为0．0252、0．0016和0．0071）。IGF1和IGF1R及IGF1和AKT在肺腺癌中表达呈显著相关（P值分别为0．0344和0．0179）。晚期肺癌（Ⅲ＋Ⅳ）IGF1和IGF1R表达显著高于早期（Ⅰ＋Ⅱ）（P值分别为0．0109和0．0303）。IGF1、IGF1R和AKT在伴有淋巴结转移肺癌中的表达显著高于无淋巴结转移肺癌（P值分别为0．0468、0．0490和0．0443）。低分化肺癌中IGF1和IGF1R表达显著高于中或高分化肺癌（P值分别为0．0484和0．0291）。IGF1和IGF1R阳性患者的生存时间显著短于阴性者（IGF1：10比14个月，P=0．0103；IGF1R：13比26个月，P=0．0056）。IGF1和IGF1R是肺腺癌预后的影响因素，AKT无预后意义。结论IGF信号通路关键蛋白IGF1、IGF1R和AKT表达在肺腺癌的发生和发展中可能起重要作用，进一步的研究有望展示其在肺癌预后和治疗方面的意义。     

FGFR1和IGF1R在肺鳞癌中的表达及其临床意义

目的 探讨成纤维生长因子受体1（FGFR1）、胰岛素样生长因子受体1（IGF1R）在肺鳞癌组织中的表达及两者的临床意义。方法 采用免疫组化法检测260例肺鳞癌术后患者的癌组织及40例癌旁正常组织中FGFR1、IGF1R的表达,分析两者表达与临床病理特征及预后的关系。采用Kaplan-Meier法进行生存分析,用Cox回归模型分析影响肺鳞癌预后的独立因素。结果 FGFR1、IGF1R在肺鳞癌组织中的阳性表达率分别为51.92％（135／260）、55.4％（144／260）,均明显高于癌旁正常组织的32.5％（13／40）、30.0％（12／40）,差异均有统计学意义（P＜0.05）。FGFR1在肺鳞癌组织中的表达与吸烟、淋巴结转移有关,IGF1R表达仅与淋巴结转移有关（P＜0.005）。FGFR1、IGF1R蛋白阳性表达者的中位OS分别为38.21个月、38.48个月,均低于阴性表达者的42.55个月、42.51个月（P＞0.05）。Cox多因素分析显示,FGFR1、IGF1R表达及淋巴结转移为肺鳞癌患者术后的独立预后因子。结论 FGFR1、IGF1R均参与了肺鳞癌的发生、发展,并且二者均为肺鳞癌的不良预后指标,并有望成为分子靶向治疗的新靶点。     

IGF1R和IGFBP3在肺鳞癌中的表达及其临床意义

目的:检测IGF1R、IGFBP3在肺鳞癌组织中的表达,并探讨其在肺鳞癌发生发展中的作用及其临床意义。方法:用免疫组化二步法检测246例肺鳞癌术后组织与40例癌旁正常组织中IGF1R、IGFBP3的表达情况,并分析二者的相关性及与临床病理特征和预后的关系。结果:IGF1R在肺鳞癌组织中的阳性表达明显高于癌旁正常组织,其表达率分别为54.07%、32.5%,IGFBP3在肺鳞癌组织中的阳性表达明显低于癌旁正常组织,其表达率分别为61.79%、87.5%,差异具有统计学意义（P＜0.05）。IGF1R的表达与淋巴结转移正相关（P＜0.05）,IGFBP3的表达与肺癌的TNM分期、淋巴结转移负相关（P＜0.01）,而与其他临床病理参数无关（P＞0.05）。IGF1R阳性表达组患者生存期明显短于IGF1R阴性表达组患者,IGFBP3阳性表达组患者生存期明显长于IGFBP3阴性表达组患者,差异有统计学意义（P分别为<0.001和=0.001）。Cox单因素分析显示TNM分期、淋巴结转移、IGF1R及IGFBP3的表达均与预后相关,将TNM分期、淋巴结转移、IGF1R及IGFBP3的表达进行Cox回归多因素分析,结果显示TNM分期、IGF1R及IGFBP3的表达均为肺鳞癌患者的独立预后因子。IGF1R、IGFBP3在肺鳞癌组织中表达呈负相关（r=-0.204,P＜0.001）。结论:IGF1R、IGFBP3参与了肺鳞癌的发生、发展,并且二者均为肺鳞癌的独立预后因子。有望成为分子靶向治疗的新靶点。     

肺腺癌中表皮生长因子受体基因突变与拷贝数的检测分析

目的检测肺腺癌组织中表皮生长因子受体（EGFR）19、21外显子基因突变和拷贝数,分析EGFR基因突变和拷贝数变化的相关性。方法应用荧光定量PCR技术和荧光原位杂交（FISH）技术分别检测58例肺腺癌患者肿瘤组织中的EGFR基因突变和基因扩增,用X^2检验进行数据分析。结果58例肺腺癌患者组织中,EGFR19、21外显子突变率为43．1％（25／58）,其中2例存在两种类型的突变。EGFR基因拷贝数增加阳性率为51．7％（30／58）,包括8例扩增,22例高多体扩增。不同分化程度的肺腺癌组织间,扩增阳性率差异无统计学意义（P〉0．05）,低分化癌的突变率低于高、中分化癌（P〈O．05）。EGFR基因突变与EGFR基因拷贝数之间显著相关（P〈0．01）。结论肺腺癌组织具有较高的EGFR基因突变率和扩增阳性率;联合检测EGFR基因拷贝数和基因突变,更有利于靶向药物的筛选。     

COX-2和EGFR在肺腺癌组织中的表达及其临床意义

目的探讨环氧合酶-2（COX-2）和表皮生长因子受体（EGFR）在人肺腺癌（pulmonary adenocarcinoma，PAC）组织中的表达及其临床意义。方法应用免疫组织化学二步法（非生物素）检测56例PAC、15例癌旁增生肺组织和10例正常肺组织中COX-2和EGFR蛋白的表达。结果COX-2、EGFR蛋白在PAC中的阳性率分别为75．00％、51．79％。在PAC中COX-2、EGFR蛋白的阳性率分别与癌旁增生肺组织、正常肺组织相比，差异均有统计学意义（P〈0．01）。COX-2蛋白表达与患者吸烟、肺腺癌的组织学分级、TNM分期以及淋巴结转移均密切相关（P〈0．05）：而EGFR蛋白表达仅与PAC患者的组织学分级、TNM分期、淋巴结转移密切相关（P〈0．05）。在56例人肺腺癌巾，COX-2、EGFR蛋白表达之间呈显著正相关（P=0．001，r=0．433）。结论COX-2和EGFR在人PAC巾呈高表达，二者可能协同促进PAC的发生发展以及侵袭和转移。     

上皮-间质转化和胰岛素样生长因子Ⅰ型受体在非小细胞肺癌EGFR-TKIs获得性耐药中的作用

目的:探讨上皮-间质转化(epithelial-mesenchymal transition,EMT)和胰岛素样生长因子Ⅰ型受体(insulin-like growth factor Ⅰ receptor,IGF-1R)在非小细胞肺癌(non-small cell lung cancer,NSCLC)对表皮生长因子受体-酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitors,EGFR-TKIs)获得性耐药中的作用.方法:选用EGFR基因突变型和野生型的人肺腺癌细胞PC-9和H460,分别用吉非替尼和厄洛替尼将其诱导成耐药的PC-9/ZD和H460/ER细胞.MTT法检测各组细胞的增殖情况,划痕实验及Transwell侵袭实验检测细胞迁移和侵袭能力,蛋白质印迹法和RT-PCR法分别检测IGF-1R及EGFR信号通路分子及EMT相关分子的蛋白和mRNA表达.结果:PC-9/ZD和H460/ER为EGFR-TKI获得性耐药细胞,分别对吉非替尼和厄洛替尼的敏感性显著下降,差异有统计学意义(P＜0.05).与PC-9和H460细胞相比,耐药的PC-9/ZD和H460/ER细胞形态呈现间质细胞表型,细胞侵袭和迁移能力增加(P＜0.05).PC-9/ZD和H460/ER细胞中间质标志分子vimentin的mRNA和蛋白表达量均显著增加(P＜0.05),PC-9/ZD细胞的E-cadherin表达量显著减少(P＜0.05).与PC-9和H460细胞相比,PC-9/ZD与H460/ER细胞的IGF-1R及其磷酸化蛋白表达量显著增加(P＜0.05),AKT和ERK磷酸化水平明显上调(P＜0.05).PC-9/ZD细胞的EGFR磷酸化水平与PC-9细胞相比未见明显差异(P＞0.05),而H460/ER细胞的EGFR磷酸化水平较H460细胞显著降低(P＜0.05).结论:EGFR突变型PC-9细胞和野生型H460细胞的获得性耐药细胞中均发生了EMT,并且IGF-1R信号蛋白表达增多,提示EMT及IGF-1R信号转导通路均可能在NSCLC的EGFR-TKIs获得性耐药中起重要作用.     

RegⅣ、EGFR、PI3K蛋白在胃腺癌中的表达及意义

目的：研究再生基因蛋白Ⅳ（ Regenerating gene typeⅣ,RegⅣ）、表皮生长因子受体（ Epider-mal growth factor receptor ,EGFR）及磷脂酰肌醇3-激酶（ Phosphatidylinositol -3-kinase,PI3K）蛋白在胃腺癌中的表达及临床意义。方法应用S-P免疫组化技术检测73例胃腺癌及其相应的癌旁正常组织中RegⅣ、EGFR和PI3K蛋白的表达情况。结果73例胃腺癌组织中RegⅣ、EGFR、PI3K蛋白的阳性表达率分别为50．7％（37/73）、56．2％（41/73）、69．9％（51/73）均高于癌旁正常组织20．5％（15/73）、19．2％（14/73）、21．9％（16/73）,差异具有统计学意义（ P＜0．05）;RegⅣ的表达与肿瘤分化程度相关,差异有统计学意义（P＜0．05）;EGFR蛋白的表达与浸润深度、淋巴结转移、临床分期相关,差异有统计学意义（P＜0．05）;PI3K蛋白的表达与肿瘤分化程度、浸润深度、淋巴结转移、临床分期相关有统计学意义（P＜0．05）。 RegⅣ与EGFR、PI3K蛋白在胃腺癌组织中的表达呈正相关（r＝0．343、0．248,P＜0．05）,EGFR与PI3K蛋白在胃腺癌组织中的表达呈正相关（ r＝0．384,P＜0．05）。结论 RegⅣ可能通过激活EGFR/PI3K/Akt信号通路在胃腺癌的发生发展中发挥重要作用。     

COX-2和EGFR在人肺腺癌组织中的表达及其意义

目的探讨环氧合酶-2（COX-2）和表皮生长因子受体（EGFR）在人肺腺癌（PAC）组织中的表达及其临床意义。方法应用免疫组织化学SP法检测39例PAC组织中COX-2和EGFR的蛋白表达。结果COX-2、EGFR蛋白在PAC中的阳性率分别为：76．92％、53．85％。在PAC中COX-2、EGFR蛋白的阳性率分别与癌旁增生肺组织、正常肺组织相比，差异均有极显著性（P〈0．01）。COX-2的蛋白表达与病人吸烟、肺腺癌的分化程度、TNM分期以及淋巴结转移均密切相关（P〈0．05）。而EGFR的蛋白表达仅与PAC病人的TNM分期、淋巴结转移之间密切相关（P〈0．05）。在39例人肺腺癌中，COX-2、EGFR蛋白表达之间呈显著正相关（P=0．006，r=0．470）。结论COX-2和EGFR在人PAC中呈高表达，二者可能协同促进PAC的发生发展以及侵袭和转移。     

化疗联合或不联合EGFR-TKI治疗EGFR-TKI获得性耐药晚期肺腺癌患者的临床观察

目的:观察化疗联合或不联合表皮生长因子受体-络氨酸激酶抑制剂（EGFR-TKI）治疗晚期获得性 EGFR-TKI耐药肺腺癌患者的临床疗效及不良反应。方法:收集 2011年1月至2015年12月南通市第一人民医院治疗晚期获得性EGFR-TKI耐药肺腺癌患者60例, 采用随机数字表法分为研究组（化疗联合EGFR-TKI) 30例和对照组（单纯化疗) 30例,对比两组近期疗效、血清肿瘤标志物指标及不良反应发生情况。结果:研究组的近期疗效缓解率（20.0%)高于对照组(16.6%),但差异无统计学意义(P＞0.05);两组皮疹、恶心、呕吐及肝功能损害发生率差异有统计学意义(P＜0.05);治疗后研究组的血清癌胚抗原（CEA)、神经元特异性烯醇化酶（NSE)、细胞角质蛋白19（CK19）片段（CYFRA 21-1） 水平与对照组相似,差异无统计学意义（P＞0.05)。结论:对于EGFR-TKI耐药的晚期肺腺癌患者,单纯化疗方案更有优势。     

IGF1信号通路IGF1 IGF1R及AKT在卵巢癌顺铂耐药中表达的研究

  目的  检测IGF信号通路关键蛋白IGF1、IGF1R及AKT在卵巢癌患者血清及组织中的表达。  方法  ATP-TCA法对卵巢癌标本进行药敏试验,ELISA法检测顺铂耐药和敏感组患者血清中IGF1、IGF1R及P-AKT的表达,免疫组织化学检测卵巢癌组织中IGF1、IGF1R、Akt的表达。自患者完成化疗出院后每个月复查CA125,如CA125有异常则行影像学检查,随访时间1年。  结果  IGF1、IGF1R及AKT在卵巢癌顺铂耐药组的表达显著高于敏感组（P=0.000 1）,免疫组织化学结果显示顺铂耐药组和敏感组IGF1、IGF1R及AKT的表达相比较差异有统计学意义（P＜0.05）。随访顺铂敏感组24例中有18例患者超过1年CA125处于正常值;6例患者超过半年CA125处于正常值;耐药组中有16例患者化疗结束后半年内CA125上升高于正常值,彩超或MRI检查提示有复发病灶。  结论  IGF信号通路关键蛋白可能参与卵巢癌顺铂耐药,IGF1可能作为卵巢癌靶向治疗的新靶点。      

不同病理分期肺腺癌EGFR、ALK基因状态与EGFR-TKI靶向治疗的关系

目的：探讨不同病理分期肺腺癌表皮生长因子受体（EGFR）、间变性淋巴瘤激酶（ALK）基因状态与EGFR-TKI靶向治疗的关系。方法选取接受EGFR-TKI靶向治疗的肺腺癌患者87例,检测患者EGFR、ALK基因状态,分析其与临床特征及疗效的关系。结果 EGFR突变患者与非EGFR突变患者年龄、性别及TNM分期比较,差异无统计学意义（P﹥0.05）;EGFR突变患者吸烟比例低于非EGFR突变患者（26.32%vs 48.98%）,差异有统计学意义（P﹤0.05）;ALK阳性与ALK阴性患者的性别、吸烟比例及TNM分期比较,差异均无统计学意义（P﹥0.05）;ALK阳性患者平均年龄低于ALK阴性患者,差异有统计学意义（P﹤0.05）;EGFR突变患者EGFR-TKI治疗的总缓解率优于ALK阳性和WT/WT患者,差异均有统计学意义（P﹤0.05）;ALK阳性患者和WT/WT患者治疗疗效比较,差异无统计学意义（P﹥0.05）。结论肺腺癌患者应首先进行EGFR检测,如有条件可同时检测EGFR突变和ALK重排;EGFR突变患者应首选EGFR-TKI靶向治疗。     

肺腺癌组织EGFR突变与p53和COX-2表达相关性及其临床意义

目的 针对表皮生长因子受体(epidermal growth factor receptor,EGFR)敏感突变的酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)治疗已成为肺癌精准治疗的典范,但多数患者在EGFR-TKI治疗有效后的8～16个月不可避免会出现获得性耐药.本研究探讨p53和COX-2在EGFR突变型晚期肺腺癌组织中的表达及其与患者临床特征的关系,并观察其表达对EGFR-TKI疗效的影响.方法 选取2014-03-01-2016-01-31于郑州大学第二附属医院病理确诊为EGFR突变型晚期肺腺癌并接受EGFR-TKI治疗的43例患者,利用免疫组织化学法检测p53和COX-2在EGFR突变型晚期肺腺癌组织中的表达;x2检验分析其与临床特征之间的相关性;生存分析采用Kaplan-Meier法;并进一步对影响患者无进展生存期(progression-free survival,PFS)的因素采用Cox比例风险回归模型分析.结果 43例EGFR突变型晚期肺腺癌患者中,p53、COX-2表达阳性率分别为41.8％和53.4％.p53表达随年龄增长(x2=3.939,P=0.047)及肿瘤分化程度减低(x2=4.182,P=0.041)而升高.COX-2表达与年龄、性别、吸烟史、肿瘤分化程度、临床分期及EGFR基因突变类型均未见明显相关性(P＞0.05).p53与COX-2表达无明显相关性,P＞0.05.患者接受EGFR-TKI治疗后,p53阴性组和阳性组中位PFS分别为12.0和7.5个月,差异有统计学意义,x2=4.726,P=0.030;COX-2阴性组和阳性组中位PFS分别为12.0和10.0个月,差异有统计学意义,x2=5.578,P=0.018.进一步行多因素Cox比例风险回归模型分析显示,p53 (HR=0.450,P=0.046)和COX-2(HR=0.424,P=0.021)表达均为EGFR突变型晚期肺腺癌患者PFS的独立影响因素.结论 EGFR突变型晚期肺腺癌组织中,p53和COX-2表达可能促进肿瘤进展,有望成为EGFR-TKI疗效的预测因子.     

EGFR-TKI获得性耐药晚期肺腺癌的临床特点分析

目的探讨携带表皮生长因子受体(EGFR)敏感基因突变的晚期肺腺癌患者经过一线EGFR酪氨酸激酶抑制剂(EGFR-TKI)治疗出现获得性耐药的临床特点。方法收集2011年1月至2015年12月携带EGFR敏感基因突变的193例患者,其中一线给予吉非替尼或埃克替尼治疗120例,分析EGFR-TKI治疗过程中疗效及EGFR突变类型与出现获得性耐药时临床进展特点的关系。结果一线行EGFR-TKI治疗的120例患者中无1例获完全缓解,获部分缓解(PR)80例(66.7%),中位无进展生存时间(PFS)为12.1个月;获稳定(SD)36例(30.0%),中位PFS为6.1个月,两者PFS的差异有统计学意义(P<0.05)。获PR和SD的116例患者中,EGFR 19号外显子缺失64例(55.2%),中位PFS为11.0个月;21号外显子L858R点突变52例(44.8%),中位PFS为8.6个月,两者PFS的差异有统计学意义(P<0.05)。出现获得性耐药时50例(43.1%)仅有原发病灶进展,66例(56.9%)出现了新的转移病灶。出现获得性耐药时肺部病灶进展最多(37.9%),其次是颅内转移(26.7%)。疗效评价为PR和SD及EGFR外显子19缺失和L858R突变的患者出现获得性耐药与转移部位无关,与新发或原发病灶亦无关(P>0.05)。结论携带EGFR敏感基因突变患者经EGFR-TKI治疗后出现获得性耐药的患者,肺部病灶进展最多,其次是颅内转移。转移部位与治疗疗效及EGFR突变基因型无明显关系。     

High Coexpression of Both EGFR and IGF1R Correlates With Poor Patient Prognosis in Resected Non–Small-Cell Lung Cancer

BackgroundRecent experimental and biomarker evidence indicates that the epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor 1 (IGF1R) interact in the pathogenesis of malignant epithelial tumors, including lung cancer. This study examines the expression of both receptors and their prognostic significance in surgically resected non–small-cell lung cancer (NSCLC).MethodsEGFR and IGF1R expression were evaluated in 184 patients with NSCLC (83 squamous cell carcinomas [SCCs], 83 adenocarcinomas [ADCs], and 18 other types) using immunohistochemical (IHC) analysis. Expression of both receptors was examined in matched fresh frozen normal and tumor tissues from 40 patients with NSCLC (20 SCCs and 20 ADCs) by Western blot analysis.ResultsHigh EGFR expression was detected in 51% of patients, and SCCs had higher EGFR expression than did non-SCCs (57.4% vs. 42.5%; P = .028). High IGF1R expression was observed in 53.8% of patients, with SCC having higher expression than non-SCC (62.6% vs. 37.3%; P = .0004). A significant association was shown between EGFR and IGF1R protein overexpression (P < .005). Patients with high expression of both receptors had a poorer overall survival (OS) (P = .04). Higher EGFR and IGF1R expression was detected in resected tumors relative to matched normal tissues (P = .0004 and P = .0009), with SCC having higher expression levels than ADC.ConclusionOur findings indicate a close interrelationship between EGFR and IGF1R. Coexpression of both receptors correlates with poor survival. This subset of patients may benefit from treatments cotargeting EGFR and IGF1R.     

TM4SF4 overexpression in radiation-resistant lung carcinoma cells activates IGF1R via elevation of IGF1

Transmembrane 4 L six family member 4 (TM4SF4) is a member of the tetraspanin L6 domain family. Other members of this family, TM4SF1 (also known as L6-Ag) and TM4SF5, have been shown to be upregulated in multiple tumors and involved in epithelial-to-mesenchymal transition and cell migration. However, unlike its homologs, little is known about TM4SF4. Here, we show that TM4SF4 was highly expressed in radiation-resistant lung adenocarcinoma cells, such as A549 and Calu-3 cells, and its expression activated cell growth, migration, and invasion. Overexpression of TM4SF4 in A549 cells increased the activation of PI3K, AKT, and NF-kappaB and the expression of PTEN. IGF1R was clearly activated by overexpression of TM4SF4, although EGFR was also slightly activated. TM4SF4 expression was correlated with the increased expression of IGF1, consequently resulting in IGF1R activation. Tumorigenic activity of TM4SF4 in lung adenocarcinoma cells was also demonstrated by xenograft assay; however, this activity was almost completely suppressed by treatment with anti-TM4SF4 antibody. Our results suggest that TM4SF4 overexpression in lung carcinoma cells results in resistance to radiotherapy via IGF1-induced IGF1R activation and blocking the activity of TM4SF4 using specific antibody can be a promising therapeutics against TM4SF4-overexpressing lung adenocarcinoma.     

Depletion of insulin-like growth factor 1 receptor increases radiosensitivity in colorectal cancer

BackgroundAlthough radiation therapy for advanced colorectal cancer (CRC) is very effective in some patients, treatment resistance limits its efficacy. Insulin-like growth factor 1 receptor (IGF1R) can affect tumor responsiveness and sensitivity to radiation in several cancer types. Herein, we studied the underlying function of IGF1R in the resistance of advanced CRC to radiation therapy and the possible use of drugs targeting IGF1R to overcome this resistance in patients with CRC.MethodsDifferences in the expression levels of the IGF1R were assessed in CRC samples from patients who were radiosensitive or radioresistant. Two radio-resistant colorectal cancer cell lines, SW480 and HT29, were selected for in vitro studies, and the involvement of the IGF1R in their radiation resistance was elucidated by suppressing its expression through a targeted siRNA and through the use of a specific IGF1R inhibitor, BMS-754807. We assessed radiosensitivity in these human CRC cells lines by examining their proliferation and colony formation, as well as cell cycle analysis. Activation of the Akt pathway was assessed using western blotting.ResultsCompared with tissues from radiosensitive patients, higher IGF1R expression levels were found in patients with radiation-resistant colorectal cancer, while BMS-754807 had improved radiosensitivity and reversed radiation tolerance in both colorectal cancer cell lines. Pre-treatment with BMS-754807 prior to irradiation inhibited Akt phosphorylation, induced cell cycle arrest, and increased DNA damage. Therefore, the IGF1R contributes to radiation resistance of CRC cells in vitro.ConclusionsThis study supports the notion that the radiosensitivity of radiation-resistant colorectal cancer cells can be enhanced by directly targeting IGF1R expression or activity. Ultimately, the combination of radiotherapy with IGF1R targeted inhibitors could potentially increase its effectiveness in the treatment of advanced colorectal cancer.     

mPRα mediates P4/Org OD02-0 to improve the sensitivity of lung adenocarcinoma to EGFR-TKIs via the EGFR-SRC-ERK1/2 pathway

The discovery of epidermal growth factor receptor (EGFR) mutations has made EGFR tyrosine kinase inhibitors (EGFR-TKIs) a milestone in the treatment for advanced non–small cell lung cancer (NSCLC). However, patients lacking EGFR mutations are not sensitive to EGFR-TKI treatment and the emergence of secondary resistance poses new challenges for the targeted therapy of lung cancer. In this study, we identified that the expression of membrane progesterone receptor α (mPRα) was associated with EGFR mutations in lung adenocarcinoma patients and subsequently affected the efficacy of EGFR-TKIs. Progesterone (P4) or its derivative Org OD02-0 (Org), which is mediated by mPRα, increases the function of EGFR-TKIs to suppress the proliferation, migration, and invasion of lung adenocarcinoma cells in vitro and in vivo. In addition, the mPRα pathway triggers delayed resistance to EGFR-TKIs. Mechanistic investigations demonstrated that the mPRα pathway can crosstalk with the EGFR pathway by activating nongenomic effects to inhibit the EGFR-SRC-ERK1/2 pathway, thereby promoting antitumorigenic effects. In conclusion, our data describe an essential role for mPRα in improving sensitivity to EGFR-TKIs, thus rationalizing its potential as a therapeutic target for lung adenocarcinomas.     

The insulin‐like growth factor 1 receptor causes acquired resistance to erlotinib in lung cancer cells with the wild‐type epidermal growth factor receptor

Epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitor (TKI) therapy often provides a dramatic response in lung cancer patients with EGFR mutations. In addition, moderate clinical efficacy of the EGFR‐TKI, erlotinib, has been shown in lung cancer patients with the wild‐type EGFR. Numerous molecular mechanisms that cause acquired resistance to EGFR‐TKIs have been identified in lung cancers with the EGFR mutations; however, few have been reported in lung cancers with the wild‐type EGFR. We used H358 lung adenocarcinoma cells lacking EGFR mutations that showed modest sensitivity to erlotinib. The H358 cells acquired resistance to erlotinib via chronic exposure to the drug. The H358 erlotinib‐resistant (ER) cells do not have a secondary EGFR mutation, neither MET gene amplification nor PTEN downregulation; these have been identified in lung cancers with the EGFR mutations. From comprehensive screening of receptor tyrosine kinase phosphorylation, we observed increased phosphorylation of insulin‐like growth factor 1 receptor (IGF1R) in H358ER cells compared with parental H358 cells. H358ER cells responded to combined therapy with erlotinib and NVP‐AEW541, an IGF1R‐TKI. Our results indicate that IGF1R activation is a molecular mechanism that confers acquired resistance to erlotinib in lung cancers with the wild‐type EGFR.