EGFR-TKIs获得性耐药机制及耐药后治疗方案探讨

以表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）为代表的分子靶向药物治疗肿瘤,可明显延长非小细胞肺癌患者的无进展生存期和改善患者的生活质量,但面临耐药以及耐药后如何继续治疗等问题。阐述EGFR-TKI的作用机制和获得性耐药机制,分别对耐药后快速进展、缓慢进展和局部进展3种进展情况提出了诊疗意见,以期为改善耐药、加强疗效提供借鉴。     

非小细胞肺癌EGFR-TKI治疗失败后小细胞肺癌转化

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)的耐药分子机制逐渐明了,其中小细胞肺癌(SCLC)转化引发了学者极大关注。这种表型转化和伴发EGFR突变是肿瘤细胞异质性,或是肿瘤干细胞,或是某些分子事件使然,但无论那种机制均是推测且无直接证据。目前临床实践中对这种EGFR-TKI耐药转化为SCLC患者的治疗仅是经验分享,亦无更高级别的证据推荐。     

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方案选择

目的：介绍表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）耐药后治疗方案的选择依据及优势。方法：根据近年来的相关文献和指南进行综述,对EGFR-TKI耐药后治疗方案的适用人群及临床疗效进行综述。结果和结论：EGFR活性突变的非小细胞肺癌已经成为一种特殊的临床疾病,EGFR-TKI已经作为晚期患者的一线治疗首选方案,中位进展时间为11~14个月。对于EGFR-TKI耐药后的机制及治疗方案的研究是本领域的热点。已经发现耐药机制有EGFR 的二次突变（T790M突变）、c-Met的扩增、激活途径的改变（IGF-1,HGF,PI3CA,AXL）、转化为间充质细胞或出现小细胞特征以及肿瘤的异质性等,针对相应耐药机制的药物正在研究中。对在新药物没有临床应用之前,有几种治疗方案可供选择。     

非小细胞肺癌表皮生长因子受体–酪氨酸激酶抑制剂的研究进展及其耐药后治疗策略

肺癌是全球死亡率最高的癌症之一,非小细胞肺癌占肺癌总人群的85%以上。约2/3的非小细胞肺癌患者在诊断时已为晚期,内科治疗是晚期非小细胞肺癌患者的主要治疗手段。近些年随着靶向治疗药物表皮生长因子受体–酪氨酸激酶抑制剂（EGFR-TKI）分子治疗的出现,非小细胞肺癌患者的治疗取得了明显的成效。但是EGFR-TKI耐药问题也接踵而至,总结了非小细胞肺癌患者EGFR-TKI治疗进展以及耐药后的治疗策略,为临床选择适合患者个体化治疗方案提供参考。     

表皮生长因子受体酪氨酸激酶抑制剂（EGFRTKI） 继发性耐药的机制及对策

肺癌是最常见的恶性肿瘤之一,也是目前癌症死亡的首要原因,其中约80％为非小细胞肺癌（Nonsmall\r\nCell Lung Cancers,NSCLC）。表皮生长因子受体（Epidermal Growth Factor Receptor,EGFR）驱动基因在肺癌的发生发展过程中起重要作用,近年来,以吉非替尼和厄洛替尼为代表的表皮生长因子受体酪氨酸激酶抑制剂（Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors,EGFR-TKI）在NSCLC 的分子靶向治疗中发挥了巨大的作用,给NSCLC 患者带来了福音。然而,无论近期效果如何,最终患者都不可避免地产生耐药及病情进展。本文主要对近年来EGFR-TKI 继发性耐药的发生机制及耐药后的对策作一综述,以期更好地指导NSCLC 的治疗。     

非小细胞肺癌中EGFR突变与EGFR-TKI临床敏感性及耐药性的研究进展

目的阐述非小细胞肺癌(NSCLC)中表皮生长因子受体(EGFR)突变与表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)临床敏感性及耐药性之间的关系。方法分析总结已经发表的国内外相关文献,对非小细胞肺癌治疗中EGFR-TKI的敏感性和耐药性进行介绍。结果在NSCLC患者中用EGFR-TKI治疗有效性和EGFR活化性突变有着紧密的联系,二者都在亚洲人种,女性,不吸烟,腺癌患者中发生率较高;患者对EGFR-TKI耐药不仅与EGFR二次突变有关,还与KRAS突变,HER2过表达,蛋白酪氨酸磷酸酶基因(PTEN)缺失,胰岛素样生长因子受体1(IGFR-1)过表达等有联系。结论EGFR突变可作为临床衡量EGFR-TKI敏感性指标;耐药机制复杂多变,目前还没有完全研究清楚。     

EML4-ALK融合介导EGFR-TKI耐药晚期肺腺癌个案报告

表皮生长因子受体（EGFR）基因突变和间变性淋巴瘤激酶（ALK）基因融合的发现显著改变了非小细胞肺癌的治疗模式，并使患者生存显著获益。ALK融合突变是EGFR酪氨酸激酶抑制剂（TKI）耐药的机制之一。我们报告了1例64岁晚期肺腺癌女性患者，其存在EGFR突变，并在EGFR-TKI耐药后发生了ALK融合，通过先后使用EGFR-TKI或ALK-TKI获得了长期生存，为ALK融合介导的EGFR-TKI耐药患者的靶向治疗药物选择提供参考。     

晚期非小细胞肺癌靶向治疗的研究进展

生物标志物检测使得许多晚期非小细胞肺癌(NSCLC)患者获益。近年来,针对表皮生长因子受体(EGFR)和间变性淋巴瘤激酶(ALK)突变呈阳性的NSCLC患者,以吉非替尼、厄洛替尼、阿法替尼为代表的表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)和以克唑替尼为代表的ALK-TKI取得了卓越的疗效。但是,大多数第一代EGFR-TKI和ALK-TKI的疗效因为不可避免的继发性耐药而被减弱。目前,第三代EGFR-TKI正是基于第二代EGFR-TKI的耐药机制研发而成。除此之外,还有许多针对其他突变位点的晚期NSCLC维持治疗的靶向抑制剂。遗憾的是,针对突变比例最大的K-RAS突变,尚无疗效确切的靶向药物。因此,基于肿瘤驱动基因突变机制的探索和靶向药物的开发是目前NSCLC的研究热点。     

表皮生长因子受体-酪氨酸激酶抑制剂治疗非小细胞肺癌研究进展

常规化疗对大多数实体瘤的疗效目前处于平台期.以与肿瘤生长相关的特定蛋白或基因为靶点的新型抗肿瘤药物[尤其是表皮生长因子受体-酪氨酸激酶抑制剂(EGFR-TKI)]及其疗法的研究近年来取得显著进展.第一代可逆EGFR-TKI吉非替尼和厄洛替尼被批准用于治疗非小细胞肺癌(NSCLC),但耐药性的出现使其临床疗效大打折扣(其中激酶域中EGFR-T790M的次级点突变在获得性耐药病例中的占比大于50％).为克服耐药性问题,可与靶标共价键结合的若干新型抑制剂(第二、三代不可逆EGFR-TKI)目前处于不同的临床研究阶段.然而,包括耐受性在内的许多临床结果仍难以解释,故药物敏感性或耐药性的新型生物标记物的识别/验证必然成为改善EGFR-TKI临床疗效的可行性研究策略.本文对EGFR-TKI的原发性/获得性耐药机制以及这些小分子EGFR-TKI治疗NSCLC的临床资料进行了较系统的综述.     

抗非小细胞肺癌药物奥希替尼研究进展

年3月22日中国食品药品监督管理局(CFDA)批准表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)奥希替尼(Osimertinib)用于治疗EGFR T790M基因突变阳性的局部晚期或转移性非小细胞肺癌(NSCLC)。奥希替尼是第三代EGFR-TKI,治疗效果显著,副作用更小,尤其适用于对第一、二代EGFR-TKI耐药或者脑转移的病人。与含铂类治疗药物的二联化学疗法相比,奥希替尼可使NSCLC病人中位无进展生存期(PFS)延长5.7个月,疾病进展风险下降70%。该文就奥希替尼的作用机制、研究历程、药效学、药动学、不良反应,耐药机制进行综述,为临床使用提供参考。     

EGFR-TKIs在NSCLC中的耐药机制及治疗策略研究进展

表皮生长因子受体（EGFR）抑制剂是目前临床治疗非小细胞肺癌（NSCLC）的一线小分子靶向药物,随着EGFR酪氨酸激酶抑制剂（EGFR-TKI）的广泛使用,其耐药现象也日趋明显,已成为其治疗NSCLC的巨大挑战。本文总结了EGFR-TKIs在NSCLC中的主要耐药机制,并对相关逆转策略的研究进展进行综述。     

基于分子理化性质特征的小样本G蛋白偶联受体靶点结合活性预测的深度学习模型

目的 制备一种人参皂苷Rk1修饰的伊曲康唑新型脂质体(R-ITZ-Lip)用于肿瘤治疗,并初步考察其体内外抗肿瘤药效。方法 采用逆向蒸发法制备R-ITZ-Lip,对其进行粒径、电位、包封率等表征研究；采用荧光显微镜和流式实验定性定量考察R-ITZ-Lip体外肿瘤细胞靶向性,采用活体和离体成像实验考察其体内肿瘤靶向性；采用MTT实验和肿瘤生长曲线考察其体内外药效。结果 R-ITZ-Lip外观呈圆形,平均粒径为(124.67±2.05)nm,包封率为(97.49±1.93)%；体外细胞摄取实验结果表明,R-ITZ-Lip能够被乳腺癌细胞4T1特异性摄取,活体和离体成像结果表明R-ITZ-Lip在4T1异种移植小鼠模型的肿瘤部位分布显著增强；MTT实验表明R-ITZ-Lip对4T1细胞表现出较好的抑制作用,IC50为1.37μg/ml,低于伊曲康唑胆固醇脂质体(C-ITZ-lip)的3.12μg/ml,4T1异种移植小鼠模型体内药效结果表明,R-ITZ-Lip有效地抑制了肿瘤的生长,R-ITZ-lip组的抑瘤率为83.54%,优于C-ITZ-lip组(73.87%)和ITZ注射液组(57.86%)。结论 构建了一种人参皂苷Rk1修饰的伊曲康唑新型脂质体,具有改善的制剂学性质,能够实现肿瘤的精准靶向,提高治疗效果。     

晚期非小细胞肺癌EGFR-TKIs获得性耐药后治疗策略研究进展

肺癌是癌症相关死亡的首要原因。非小细胞肺癌（NSCLC）约占肺癌的85%,且患者在诊断时大多为晚期。随着表皮生长因子受体（EGFR）在肺癌中被发现,针对特定基因突变的靶向治疗成为晚期NSCLC的重要治疗方式,并显著延长了患者生存期。尽管第一、二、三代EGFR-酪氨酸激酶抑制剂（TKI）蓬勃发展,但随着治疗时间的推移,患者都可能面临耐药和进展。为克服这一难题,基于耐药机制的相关治疗策略正在研究中。本文旨在对近年来EGFR-TKIs,特别是在疗效及安全性上作为指南更优推荐的第三代EGFR-TKIs的耐药机制和治疗策略的研究进展进行综述。     

Small-molecule EGFR tyrosine kinase inhibitors for the treatment of cancer

Introduction: EGFR has been implicated in various malignancies such as NSCLC, breast, head and neck, and pancreatic cancer. Numerous drugs have been developed in order to target the tyrosine domain of EGFR as an approach in cancer treatment.

Areas covered: This article focuses on the different generations of EGFR tyrosine kinase inhibitors (TKIs). This spans from the emergence of the first-generation EGFR-TKIs to overcoming drug resistance using second-generation EGFR-TKIs and to reducing adverse effect (AE) using mutant-selective third-generation EGFR-TKIs.

Expert opinion: Current TKI treatment is frequently accompanied by drug resistance and/or serious AEs. There has been the promise of advancements in second-generation EGFR-TKIs that could overcome drug resistance, acting as second- or third-line salvage treatment, but this promise has yet to be met. That being said, both issues are currently being addressed with mutant-selective EGFR-TKIs with the expectation of bringing more EGFR-targeted therapy into the next phase of cancer therapy in the future.     

NRF2-GPX4/SOD2 axis imparts resistance to EGFR-tyrosine kinase inhibitors in non-small-cell lung cancer cells

Epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs)have achieved satisfactory clinical effects in the therapy of non-small cell lung cancer(NSCLC),but acquired resistance limits their clinical application.NRF2 has been shown to enhance the resistance to apoptosis induced by radiotherapy and some chemotherapy.In this study,we investigated the role of NRF2 in resistance to EGFR-TKIs.We showed that NRF2 protein levels were markedly increased in a panel of EGFR-TKI-resistant NSCLC cell lines due to slow degradation of NRF2 protein.NRF2 knockdown overcame the resistance to EGFR-TKIs in HCC827ER and HCC827GR cells.Furthermore,we demonstrated that NRF2 imparted EGFR-TKIs resistance in HCC827 cells via upregulation of GPX4 and SOD2,and suppression of GPX4 and SOD2 reversed resistance to EGFR-TKIs.Thus,we conclude that targeting NRF2-GPX4/SOD2 pathway is a potential strategy for overcoming resistance to EGFR-TKIs.     

Targeting epidermal growth factor receptor: Central signaling kinase in lung cancer

Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. Platinum-based doublets remain the current standard therapy for advanced NSCLC. However, overall survival (OS) has reached a plateau, even with the improvement in these regimens. Advances in the knowledge of molecular mechanisms of carcinogenesis have prompted the development of many novel molecular-targeted agents including the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Results of the recent phase III IPASS trial showed that the EGFR-TKI gefitinib has a superior progression-free survival (PFS) to the most commonly used platinum-based doublet carboplatin-paclitaxel as the first-line chemotherapy for pulmonary lung adenocarcinoma among nonsmokers in East Asia. This trial also demonstrated that the presence of EGFR mutation is the best predictor of gefitinib treatment compared with the other biomarkers including EGFR gene copy number. Despite the therapeutic benefit of EGFR-TKIs in NSCLC, most patients eventually develop resistance to these drugs. A secondary mutation of EGFR (T790M) and amplification of MET account for 70% of all cases of acquired resistance to EGFR-TKIs. This review summarizes the significance of EGFR mutations and the mechanisms of resistance to EGFR-TKIs in NSCLC, both of which are critical for patient selection to extend survival as well as to overcome resistance in NSCLC patients treated with EGFR-TKIs.     

阿美替尼治疗非小细胞肺癌的研究进展

肺癌是全球癌症相关死亡的最常见原因,其中85%为非小细胞肺癌(non-small-cell lung cancer,NSCLC),表皮生长因子受体(epidermal growth factor receptor,EGFR)是治疗晚期NSCLC最重要的靶点之一。第一、二代EGFR酪氨酸激酶抑制剂(EGFR-tyrosine kinase inhibitor,EGFR-TKI)一直是晚期EGFR突变NSCLC患者的标准治疗方法,但获得性耐药几乎不可避免,主要耐药原因为T790M突变。阿美替尼是中国首个自主研发的第三代EGFR-TKI,对包括L858R和19号外显子缺失在内的EGFR敏感突变,以及T790M耐药突变均具有活性,同时保留野生型EGFR,克服了第一、二代EGFR-TKI的耐药性和选择性问题,其临床前和临床研究均显示出良好的有效性与安全性,为我国NSCLC患者提供了新的用药选择。本综述对阿美替尼的结构、作用机制、临床前研究、药动学,在NSCLC治疗中的临床疗效、安全性,以及与其他第三代EGFR-TKI的比较进行了总结,为该药的临床使用及未来的探索研究提供参考。     

Osimertinib for EGFR T790M mutation-positive non-small cell lung cancer

Introduction: Significant advances have been made since the development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) targeting EGFR mutations in non-small-cell lung cancer (NSCLC), however, lung cancer cells eventually acquire resistance to those agents. Osimertinib (AZD9291) has been developed as 3^rd generation EGFR-TKI with activities against sensitizing mutations and T790 M resistance mutation, which account for about 50% of the mechanisms of acquired resistance to 1^st or 2^nd generation EGFR-TKIs. A recent phase I/II clinical trial with osimertinib for advanced NSCLC patients with known sensitizing EGFR mutations and documented disease progression on prior EGFR-TKIs revealed promising effect with acceptable toxicities.

Areas covered: This article summarizes current understanding and available preclinical and clinical data on osimertinib and also discusses future directions. The literature search included PubMed and the latest articles from international conferences.

Expert commentary: The development of osimertinib has provided new therapeutic options for NSCLC patients harboring T790 M. Compared with other EGFR-TKIs including rociletinib, osimertinib seems to possess an advantage with respect to the effect and safety profile among existing EGFR-TKIs. However, tumor progression still occurs even when treating with osimertinib. A further understanding of the mechanisms of resistance is eagerly anticipated in order to develop next generation EGFR-TKIs.     

Recent understanding of the molecular mechanisms for the efficacy and resistance of EGF receptor-specific tyrosine kinase inhibitors in non-small cell lung cancer

INTRODUCTION: The epidermal growth factor receptor (EGFR) and its family members are involved in many aspects of tumor biological processes. Aberrant activation of the EGFR tyrosine kinase by mutations or protein overexpression is observed in various types of human cancer, including lung cancer. EGFR tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, are highly effective in lung cancer patients who harbor active mutations in the EGFR gene. However, patients who are initially sensitive to EGFR-TKIs eventually relapse within few years. AREAS COVERED: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and is associated with a high frequency of EGFR mutations. This review describes the EGFR mutations that determine the sensitivity to EGFR-TKIs and the current understanding of the molecular mechanisms of acquired resistance to EGFR-TKIs in NSCLC. Furthermore, the authors describe recent strategies developed to overcome acquired resistance using second-generation EGFR-TKIs and combination therapies with several molecular-targeting drugs. EXPERT OPINION: Although recent findings have contributed to our understanding of the mechanism of acquired resistance and helped the development of novel strategies to overcome such resistance, the underlying mechanisms are complex and additional research is necessary to develop effective therapeutic strategies for individual patients with lung cancer.     

miR-340 与Nrf2 在非小细胞肺癌患者靶向治疗耐药中的表达及相关性分析

目的探究miR-340与Nrf2在非小细胞肺癌患者靶向治疗耐药中的表达及意义。方法选取2016年1月—2019年12月我院收治的EGFR基因突变非小细胞肺癌表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)耐药患者42例作为观察组,同期于我院治疗的非耐药患者42例为对照组,检测并比较两组患者miR-340、Nrf2表达水平,同时探究miR-340水平与Nrf2的相关性。结果观察组患者血清miR-340水平显著高于对照组(P<0.05),Nrf2水平显著低于对照组(P<0.05);miR-340与Nrf2水平呈负相关(P<0.05);进一步Logistic分析显示,miR-340表达上调及Nrf2表达下调是非小细胞肺癌患者EGFR-TKIs耐药发生的独立危险因素。结论miR-340可通过影响体内Nrf2水平参与EGFR-TKIs耐药的发生,为提高肺腺癌的诊治提供了新的理论依据及潜在干预靶点。