文章：

肺癌中的表皮生长因子受体突变

Epidermal growth factor receptor mutations in lung cancer

原文发布日期：2007-03-01

DOI: 10.1038/nrc2088

类型: Review Article

开放获取: 否

要点：

1. Advanced non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related deaths in the world.
2. Epidermal growth factor receptor (EGFR) is expressed in 50% of NSCLCs, and its expression is correlated with poor prognosis. These two factors make EGFR and its family members prime candidates for the development of targeted therapeutics.
3. Two EGFR-targeting small-molecule inhibitors, gefitinib (Iressa: AstraZeneca, approved in May 2003) and erlotinib (Tarceva: OSI-Genentech, approved in November 2004) received fast-track approval from the US Food and Drug Administration as treatment for patients with advanced NSCLC who had failed to respond to conventional chemotherapy.
4. Early clinical data showed that 10% of patients with NSCLC responded to gefitinib or erlotinib. Although infrequent, the speed and magnitude of clinical responses were unique, as was the fact that they were seen in specific subsets of cases (non-smokers, women, East Asians and patients with adenocarcinomas with bronchioloalveolar histology).
5. Molecular analysis showed that in most instances, responders harboured specific mutations in the gene that encodes EGFR. Exon 19 mutations characterized by in-frame deletions of amino-acids 747–750 account for 45% of mutations, exon 21 mutations resulting in L858R substitutions account for 40–45% of mutations, and the remaining 10% of mutations involve exon 18 and 20.
6. EGFR kinase domain mutations hyperactivate the kinase and confer a dependence on the mutated kinase for the survival of the NSCLC tumour cells.
7. The treatment of sensitive cells with targeted therapeutics such as gefitinib and erlotinib seems to trigger a form of 'oncogenic shock', which is postulated to result from the differential decay of downstream signals leading to a temporary predominance of apoptotic signals.
8. Acquired resistance to gefitinib and erlotinib might involve the recurrent mutation T790M which affects the gatekeeper residue in the catalytic domain of the kinase that weakens the interaction of the inhibitor with its target. Resistance can be overcome in vitro by irreversible inhibitors of EGFR

要点翻译：

1. 晚期非小细胞肺癌（NSCLC）是全球癌症相关死亡的主要原因。表皮生长因子受体（EGFR）在50%的非小细胞肺癌中表达，其表达与不良预后相关。这两大因素使EGFR及其家族成员成为开发靶向治疗药物的主要目标。
2. 两种靶向EGFR的小分子抑制剂——吉非替尼（易瑞沙，阿斯利康公司，2003年5月获批）和厄洛替尼（特罗凯，OSI-基因泰克公司，2004年11月获批）获得美国食品药品监督管理局快速审批，用于治疗对常规化疗无效的晚期非小细胞肺癌患者。
3. 早期临床数据显示，10%的非小细胞肺癌患者对吉非替尼或厄洛替尼产生应答。尽管应答率不高，但其临床反应的速度和程度独具特征，且在特定病例亚组（不吸烟者、女性、东亚人群及具有支气管肺泡腺癌组织学特征的患者）中尤为显著。
4. 分子分析表明，在大多数应答病例中，患者携带编码EGFR基因的特异性突变。其中第19号外显子突变（以747-750位氨基酸框内缺失为特征）占45%，第21号外显子突变（导致L858R置换）占40-45%，其余10%的突变涉及第18和20号外显子。
5. EGFR激酶结构域突变会过度激活激酶活性，导致非小细胞肺癌肿瘤细胞的存活依赖于突变激酶。使用吉非替尼、厄洛替尼等靶向药物治疗敏感细胞会引发一种"致癌休克"现象，推测这是由于下游信号差异性衰减导致凋亡信号暂时占优势所致。
6. 对吉非替尼和厄洛替尼的获得性耐药可能涉及T790M复发性突变，该突变影响激酶催化结构域的门控残基，从而削弱抑制剂与靶点的结合。体外实验表明，不可逆性EGFR抑制剂可克服此类耐药性。

英文摘要：

The development and clinical application of inhibitors that target the epidermal growth factor receptor (EGFR) provide important insights for new lung cancer therapies, as well as for the broader field of targeted cancer therapies. We review the results of genetic, biochemical and clinical studies focused on somatic mutations of EGFR that are associated with the phenomenon of oncogene addiction, describing 'oncogenic shock' as a mechanistic explanation for the apoptosis that follows the acute treatment of susceptible cells with kinase inhibitors. Understanding the genetic heterogeneity of epithelial tumours and devising strategies to circumvent their rapid acquisition of resistance to targeted kinase inhibitors are essential to the successful use of targeted therapies in common epithelial cancers.

摘要翻译： 

靶向表皮生长因子受体（EGFR）抑制剂的开发与临床应用，为肺癌新型疗法乃至更广泛的靶向癌症治疗领域提供了重要启示。我们回顾了聚焦于EGFR体细胞突变的遗传、生化及临床研究结果，这些突变与“癌基因成瘾”现象相关，并提出“癌性休克”作为易感细胞经激酶抑制剂急性处理后发生凋亡的机制解释。理解上皮性肿瘤的遗传异质性，并设计策略以规避其对靶向激酶抑制剂快速获得耐药性，是将靶向疗法成功应用于常见上皮癌的关键。

原文链接：

Epidermal growth factor receptor mutations in lung cancer