非小细胞肺癌EGFR-TKIs耐药——小细胞肺癌转化的研究进展

表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor tyrosine kinase inhibitors, EGFR TKIs)在治疗携带EGFR基因敏感突变的非小细胞肺癌(non-small cell lung cancer,NSCLC)中已取得显著疗效,但是,耐药的产生几乎是不可避免的,常见的耐药机制包括T790M突变、cMET基因扩增等.目前已有文献报道EGFR-TKI耐药的机制之一为NSCLC转化为小细胞肺癌(small cell lung cancer, SCLC),大约占3%-15%,是一种重要的少见耐药机制,并不为人们所深入了解.本文从"共同起源"和"转化时间节点"两个角度对其进行了归纳总结,重点探讨了其转化的可能机制,目前提出的两种可能转化机制分别为肿瘤异质性假说、NSCLC转化为SCLC假说,还涉及了许多分子水平的改变,如RB1基因缺失、P53基因失活、PTEN M264I基因突变等,同时对该种转化的发病特点、治疗策略等方面进行了归纳与总结.目前仍有许多问题需要进一步研究和解决.     

EGFR、TP53共突变的晚期非小细胞肺癌靶向治疗进展

摘 要：TP53突变是表皮生长因子受体(epidermal growth factor receptor,EGFR)基因突变的晚期非小细胞肺癌(non-small cell lung cancer,NSCLC) 最常见的合并体突变,在靶向治疗过程中与疾病进展和较差的预后相关。为揭示TP53突变在EGFR突变的晚期NSCLC靶向治疗中的预后价值,探讨治疗方案,国内外医学界进行了深入的研究,但尚未达成共识。全文就近年来EGFR/TP53共突变的NSCLC靶向治疗的进展进行综述,为临床治疗研究提供新思路。     

TP53-EGFR共突变对非小细胞肺癌预后及治疗的研究进展

非小细胞肺癌(Non-small cell lung cancer, NSCLC)是全球癌症相关死亡的主要原因。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)是目前NSCLC患者靶向表皮生长因子受体(Epidermal growth factor receptor, EGFR)突变的标准一线治疗方法，然而原发性或获得性耐药会导致治疗中断和疾病进展。TP53突变是EGFR突变型NSCLC患者中最常见的共突变，研究表明TP53-EGFR共突变提示患者预后不良，对这类突变患者的治疗方案尚未达成共识。本文就TP53突变在晚期EGFR突变型NSCLC患者中的预后价值和TP53-EGFR共突变晚期NSCLC患者治疗的研究进展进行综述。     

EGFR基因突变与非小细胞肺癌靶向治疗研究进展

表皮生长因子受体（epidermal growth factor receptor,EGFR）在非小细胞肺癌（non-small cell lung cancer,NSCLC）常过度表达,EGFR突变常发生在外显子18～21,与EGFR分子靶向药物的反应敏感性相关。本文就EGFR基因在NSCLC中的突变及其靶向治疗进展做一综述。     

TP53、EGFR共突变对NSCLC治疗的影响及对预后预测作用的进展

摘 要：随着二代基因检测技术的发展,人们发现与单个基因突变相比,多个体细胞共突变已被证明与预后较差有关。在这些共突变中,TP53突变最常见,但被认为是不可用药的靶点。近年来对TP53突变的预测价值进行了深入研究,由于结果不一致,尚未达到临床应用。本篇综述通过对近几年国内外关于TP53抑癌基因与EGFR共突变对非小细胞肺癌（non-small cell lung cancer,NSCLC）治疗及预后的影响进行小结,为EGFR伴随TP53突变NSCLC的靶向治疗提供新的思路。     

转化性小细胞肺癌1例分析

我国肺癌发病率及死亡率在恶性肿瘤中居首位[1]。肺癌分为小细胞肺癌(small cell lung cancer,SCLC)和非小细胞肺癌(non-small cell lung cancer,NSCLC)[2]。NSCLC包括腺癌、鳞癌及大细胞肺癌。最常见的组织学分类是腺癌,其次是小细胞癌,鳞状细胞癌或神经内分泌肿瘤次之。对于无法手术的肺腺癌患者,出现表皮生长因子受体(epidermal growth factor receptor,EGFR)突变,抗EGFR的小分子酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)为首选治疗方案[3]。虽然EGFR-TKI效果良好,但部分患者用药后发生耐药。第一代EGFR-TKI包括吉非替尼、厄洛替尼、埃克替尼等,多于用药9~11月后出现耐药[4]。该耐药机制中有一种较少见的耐药现象为病理类型转化[5]。本文报道经EGFR-TKI治疗发生病理类型转变的转化性小细胞肺癌1例。     

非小细胞肺癌对酪氨酸激酶抑制剂获得性耐药机制及治疗策略的研究进展

摘 要：表皮生长因子受体(epidermal growth factor receptor,EGFR)是非小细胞肺癌（non-small cell lung cancer,NSCLC）最常见的肿瘤驱动基因。以EGFR为靶点的酪氨酸激酶抑制剂（tyrosine kinase inhibitor,TKI）分子靶向治疗,可显著性改善携带这类基因突变的NSCLC患者的生存结局。然而,这些最初获得缓解的患者最终都会发生获得性耐药,成为进一步提高靶向药物TKI疗效的瓶颈。因此,了解TKI获得性耐药机制可指导NSCLC临床治疗。文章综述近年来NSCLC对TKI耐药机制的新进展及耐药后治疗的新策略。     

肺大细胞神经内分泌癌的分子分型及临床治疗进展

肺大细胞神经内分泌癌(large cell neuroendocrine carcinoma,LCNEC)发病率较低,占肺恶性肿瘤的2.1%~3.5%,诊断困难,治疗方案的选择尚存争议。LCNEC具有独特的基因谱及转录谱,根据TP53、RB1等基因突变及表达情况可进一步将LCNEC分为RB1野生型和RB1突变型,其中RB1野生型应用非小细胞肺癌(non-small cell lung cancer,NSCLC)常用化疗方案较小细胞肺癌(small cell lung cancer,SCLC)常用方案可显著提高总生存期(overall survival,OS),而RB1突变型应用不同的化疗方案生存均无显著性差异。针对LCNEC的靶向和免疫治疗仅见于小样本的回顾性分析及个案报道。本文对LCNEC相关的分子分型及临床治疗进展予以综述。     

EGFR靶向治疗的现状 机遇和挑战

肺癌是癌症相关死亡的主要原因。目前,肺癌的发病率正在下降,但患者的生存率仍然较低。肺癌中超过85%是非小细胞肺癌（non-small cell lung cancer, NSCLC）,超过60%的NSCLC表达表皮生长因子受体（epidermal growth factor receptor, EGFR）,该类突变在肺腺癌、女性、亚洲人群和从未吸烟的人群中更常见。EGFR已成为NSCLC的重要治疗靶点,目前已开发出多种靶向药物,包括小分子酪氨酸激酶抑制剂（tyrosine kinase inhibitors, TKIs）和单克隆抗体。EGFR-TKIs现已开发至第四代,并改写了EGFR突变型NSCLC的诊疗指南。在所有EGFR突变中,18号外显子（G719A/C）、21号外显子（L858R和L861Q）的点突变以及19号外显子框内缺失突变（Exon19 del）对TKIs高度敏感,其中Exon19 del敏感性最高。尽管EGFR靶向治疗效果显著,但几乎所有患者最终均会产生耐药。最常见的耐药突变是T790M突变,其他耐药突变包括D761Y、T854A和L747S等。本文对近几年EGFR靶向治疗的进展进行综述。      

阿帕替尼逆转阿法替尼耐药治疗EGFR20外显子插入突变晚期非小细胞肺癌1例

恶性肿瘤严重威胁人们的生命健康,尤其是肺癌。随着对肺癌分子生物学的深入研究以及相关靶向药物的开发,靶向治疗已经改变了晚期肺癌的治疗格局。目前肺癌靶向治疗耐药机制成为研究的热点。本文报道1例阿帕替尼逆转经阿法替尼治疗耐药的表皮生长因子受体(epidermal growth factor receptor-tyrosine kinase,EGFR)20外显子插入突变晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者的治疗过程,并做文献复习。     

非小细胞肺癌EGFR-TKIs耐药——小细胞肺癌转化的机制和治疗

肺癌是当前死亡率最高的恶性肿瘤之一。表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）明显提高了晚期非小细胞肺癌（NSCLC）患者的生活质量,延长了生存期。EGFR基因优势突变的NSCLC患者临床获益明显,然而由于耐药产生,患者的中位无进展生存期（PFS）仅1年左右。最近,有文献报道EGFR TKIs耐药的机制之一是NSCLC转化为小细胞肺癌（SCLC）。本文对这种现象进行了分析总结,探讨了其转化的可能机制。根据EGFR-TKIs耐药后的处理方法和病理表型转化患者的治疗报道,探讨NSCLC EGFR-TKIs耐药后转化为SCLC患者的治疗策略。     

Small cell lung cancer transformation from EGFR-mutated lung adenocarcinoma: A case report and literatures review

Epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have markedly improved the response of non-small cell lung cancer (NSCLC) with EGFR-mutant patients. However, these patients inevitably come cross acquired resistance to EGFR-TKIs. The transformation of lung adenocarcinoma to small cell lung cancer (SCLC) following treatment with EGFR-TKIs is rare, which leads to resistance to EGFR-TKIs.

The present case concerns a case of a 38-year-old man presenting with cough and dyspnea. Radical resection was performed and confirmed an EGFR exon 21 L858R lung adenocarcinoma. However, the patient suffered pleural metastasis after successful treatment with surgery and adjuvant treatment. So, erlotinib was administered with 18 months. Because of enlarged pleural nodule, repeat biopsy identified an SCLC and chemotherapy was started. However, despite the brief success of chemotherapy, our patient suffered brain metastasis.

Our case emaphsizes both the profile of transformation from NSCLC to SCLC and the importance of repeat biopsy dealing with drug resistance. We also summarize the clinical characteristics, mechanisms, predictors of SCLC transformation, treatment after transformation and other types of transformation to SCLC.     

EGFR activating aberration occurs independently of other genetic aberrations or telomerase activation in adenocarcinoma of the lung

The prognosis of lung cancer remains poor, and biological heterogeneity is largely responsible, especially in adenocarcinoma. We previously found that only one third of non-small cell lung cancer (NSCLC) but most small cell lung cancer (SCLC) tissues have strong telomerase activity, representing the difference in the history of multiple clonal selections. To reveal the genes differentially involved in telomerase activation mechanisms, we analyzed the relationship between common genetic aberrations and telomerase activity in 83 lung cancer tissues. We found that half (7 of 14) of lung adenocarcinomas with high telomerase activity showed neither TP53 nor RB1 deletion, while all squamous cell carcinomas and SCLCs with high telomerase activity showed loss of heterozygosity of at least one, if not both, of these suppressor oncogenes, indicating that these genetic aberrations are not required in activation of telomerase in a unique subset of adenocarcinoma. Furthermore, whereas the aberrations in TP53, RB1 and 1p34-pter were mutually related in 42 adenocarcinoma tissues, EGFR aberrations showed no relationship to either of them. These findings indicate that EGFR activating aberrations occur independently of other common genetic aberrations or telomerase activation mechanisms in lung adenocarcinoma, and that the distinct subset of lung adenocarcinoma with high telomerase activity without any common genetic aberrations may possibly have arisen from a telomerase-positive or telomerase-competent normal cell.     

Small-Cell Lung Cancer Transformation as a Mechanism of Resistance to Pralsetinib in RET-Rearranged Lung Adenocarcinoma: A Case Report

The majority of resistance to Rearranged during transfection (RET)-specific tyrosine kinase inhibitors (TKI) described in RET-rearranged non-small cell lung cancer (NSCLC) patients are driven by RET-independent mechanisms. We provide the first case report of a RET-rearranged lung adenocarcinoma (LUAD) transformation into small-cell lung cancer (SCLC) as a mechanism of acquired resistance to pralsetinib. A 43-year-old patient presented with a RET-rearranged LUAD revealed by pleural effusion. After 14 months of response to pralsetinib, biopsy of a progressive pleural lesion found a phenotypic transformation into SCLC. Molecular analysis identified the same RET fusion and TP53 mutation in both primary adenocarcinoma and recurrence as SCLC. The patient achieved partial response after switch to carboplatin and etoposide chemotherapy and presented with progression disease after 6 months. Histological transformation could be a mechanism of resistance to RET-TKIs and rebiopsy should be considered to adapt subsequent treatment.     

小细胞肺癌潜在治疗靶点研究进展

 小细胞肺癌（SCLC）约占肺癌的15%，致死率高。SCLC的病理、分子生物学机制和临床预后特征与非小细胞肺癌（NSCLC）不尽相同。大多数SCLC表达神经内分泌特征（整合了神经和内分泌特性），其分子机制可能与TP53和RB1的失活，以及包括Notch信号在内的多个信号通路的频繁中断有关。近年来，随着分子机制研究深入和相关的基因工程小鼠模型的开发以及建立患者来源的异种移植物模型的研究进展，为发现SCLC潜在的治疗靶点，改善疗效和预后带来了新希望。     

Transformation to small-cell lung cancer following treatment with EGFR tyrosine kinase inhibitors in a patient with lung adenocarcinoma

We report the case of a 52-year-old woman with lung adenocarcinoma treated with EGFR tyrosine kinase inhibitor (TKI) therapy. After disease progression, histological examination of a secondary biopsy specimen revealed small-cell lung cancer (SCLC) that was sensitive to standard SCLC treatment. Tumor markers, including ProGRP and NSE, were elevated. Transformation to SCLC is a mechanism for acquired resistance to EGFR-TKI therapy. Secondary biopsy is important for evaluation of genetic and histological changes and selection of appropriate treatment. Furthermore, ProGRP and NSE may be useful for early detection of SCLC transformation in cases resistant to EGFR-TKI therapy.     

28例治疗后进展肺癌重复活检的临床意义

  目的  探讨重复活检对治疗后进展肺癌的临床意义，为制定晚期肺癌的后线治疗策略提供参考。  方法  回顾性分析2019年11月至2020年6月28例于东南大学附属中大医院接受重复活检肺癌患者的临床资料，分析病灶组织重复活检前后变化差异。  结果  病理类型方面，28例肺癌中，27例为非小细胞肺癌（non-small cell lung cancer，NSCLC），1例小细胞肺癌（small cell lung can-cer，SCLC）。治疗后重复活检结果表明，3例由腺癌转变为SCLC，转化时间为18~41个月；另有3例腺癌出现肉瘤样分化。驱动基因方面，2例重复活检后出现变化，其中1例表皮生长因子受体（epidermal growth factor receptor，EGFR）阴性患者化疗后出现EGFR 19外显子缺失，1例EGFR 19外显子缺失患者经表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor-tyro-sine kinase inhibitor，EGFR-TKI）治疗后出现EGFR T790M耐药突变。  结论  肺癌治疗进展后对病灶组织及时进行重复活检，是正确评估病灶组织病理及驱动基因变化、选择新的治疗方案的重要保证。      

Targeting apoptosis pathways in lung cancer

Lung cancer is a devastating disease with a poor prognosis. Non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) represent different forms of lung cancer that are associated with distinct genetic causes and display different responses to therapy in the clinic. Whereas SCLC is often sensitive to chemotherapy at start of treatment, NSCLC are less chemo-sensitive. In NSCLC different histological subtypes are distinguished and increasing efforts are made to identify subtypes that respond to specific therapies, such as those harbouring epidermal growth factor receptor (EGFR) mutations that have benefit from treatment with EGFR inhibitors. Targeting of the apoptotic machinery represents another approach that aims to selectively kill cancer cells while sparing normal ones. Here we describe different ways that are currently explored to induce apoptosis in lung cancer cells, specifically pathways controlled by TNF-related apoptosis-inducing ligand (TRAIL), BCL-2 family members and apoptosis inhibitory proteins (IAPs). Preclinical studies are discussed and for some agents results from early clinical studies and future perspectives are considered.