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肺癌当前分子靶向治疗面临的临床挑战

Clinical Challenges to Current Molecularly Targeted Therapies in Lung Cancer.

作者信息

Chhabra Gagan, Eggert Ashley, Puri Neelu

机构信息

Department of Biomedical Sciences, University of Illinois College of Medicine, Rockford, Illinois, USA.

出版信息

Arch Cancer Res. 2015;3(3). doi: 10.21767/2254-6081.100030.

DOI:10.21767/2254-6081.100030
PMID:27280107
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4894332/
Abstract

Lung cancer is difficult to treat with a poor prognosis and a five year survival of 15%. Current molecularly targeted therapies are initially effective in non-small cell lung cancer (NSCLC) patients; however, they are plagued with difficulties including induced resistance and small therapeutically responsive populations. This mini review describes the mechanism of resistance to several molecularly targeted therapies which are currently being used to treat NSCLC. The major targets discussed are c-Met, EGFR, HER2, ALK, VEGFR, and BRAF. The first generation tyrosine kinase inhibitors (TKIs) resulted in resistance; however, second and third generation TKIs are being developed, which are generally more efficacious and have potential to treat NSCLC patients with resistance to first generation TKIs. Combination therapies could also be effective in preventing TKI resistance in NSCLC patients.

摘要

肺癌难以治疗，预后较差，五年生存率为15%。目前的分子靶向疗法最初对非小细胞肺癌（NSCLC）患者有效；然而，它们存在诸多困难，包括诱导耐药性和治疗反应性小的群体。这篇小型综述描述了目前用于治疗NSCLC的几种分子靶向疗法的耐药机制。讨论的主要靶点是c-Met、表皮生长因子受体（EGFR）、人表皮生长因子受体2（HER2）、间变性淋巴瘤激酶（ALK）、血管内皮生长因子受体（VEGFR）和B-Raf原癌基因（BRAF）。第一代酪氨酸激酶抑制剂（TKIs）产生了耐药性；然而，第二代和第三代TKIs正在研发中，它们通常更有效，并且有潜力治疗对第一代TKIs耐药的NSCLC患者。联合疗法在预防NSCLC患者的TKI耐药性方面也可能有效。

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本文引用的文献

1
Mechanism of Resistance and Novel Targets Mediating Resistance to EGFR and c-Met Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer.非小细胞肺癌中对表皮生长因子受体（EGFR）和c-Met酪氨酸激酶抑制剂耐药的机制及介导耐药的新靶点
PLoS One. 2015 Aug 24;10(8):e0136155. doi: 10.1371/journal.pone.0136155. eCollection 2015.
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Identification of a Novel ALK G1123S Mutation in a Patient with ALK-rearranged Non-small-cell Lung Cancer Exhibiting Resistance to Ceritinib.在对色瑞替尼耐药的ALK重排非小细胞肺癌患者中鉴定出一种新型ALK G1123S突变。
J Thorac Oncol. 2015 Jul;10(7):e55-7. doi: 10.1097/JTO.0000000000000509.
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Secondary mutations at I1171 in the ALK gene confer resistance to both Crizotinib and Alectinib.ALK基因中I1171位点的二次突变赋予了对克唑替尼和阿来替尼的耐药性。
J Thorac Oncol. 2014 Dec;9(12):e86-7. doi: 10.1097/JTO.0000000000000358.
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Identification of a novel HIP1-ALK fusion variant in Non-Small-Cell Lung Cancer (NSCLC) and discovery of ALK I1171 (I1171N/S) mutations in two ALK-rearranged NSCLC patients with resistance to Alectinib.在对阿来替尼耐药的两个存在 ALK 重排的非小细胞肺癌（NSCLC）患者中发现了一种新型的 HIP1-ALK 融合变体和 ALK I1171（I1171N/S）突变。
J Thorac Oncol. 2014 Dec;9(12):1821-5. doi: 10.1097/JTO.0000000000000368.
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Afatinib: A first-line treatment for selected patients with metastatic non-small-cell lung cancer.阿法替尼：特定转移性非小细胞肺癌患者的一线治疗药物。
Am J Health Syst Pharm. 2014 Nov 15;71(22):1933-8. doi: 10.2146/ajhp130654.
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Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor.发现一种有效的、选择性的 EGFR 抑制剂（AZD9291），对敏感突变和 T790M 耐药突变均有效，并且能避免野生型受体的影响。
J Med Chem. 2014 Oct 23;57(20):8249-67. doi: 10.1021/jm500973a. Epub 2014 Oct 1.
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Two novel ALK mutations mediate acquired resistance to the next-generation ALK inhibitor alectinib.两种新的ALK突变介导对下一代ALK抑制剂阿来替尼的获得性耐药。
Clin Cancer Res. 2014 Nov 15;20(22):5686-96. doi: 10.1158/1078-0432.CCR-14-1511. Epub 2014 Sep 16.
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Oral epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer: comparative pharmacokinetics and drug-drug interactions.口服表皮生长因子受体酪氨酸激酶抑制剂治疗非小细胞肺癌：比较药代动力学和药物相互作用。
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Next-generation sequencing reveals a Novel NSCLC ALK F1174V mutation and confirms ALK G1202R mutation confers high-level resistance to alectinib (CH5424802/RO5424802) in ALK-rearranged NSCLC patients who progressed on crizotinib.下一代测序揭示了一种新型 NSCLC ALK F1174V 突变，并证实 ALK G1202R 突变使对克唑替尼治疗后进展的 ALK 重排 NSCLC 患者对艾乐替尼（CH5424802/RO5424802）具有高水平耐药性。
J Thorac Oncol. 2014 Apr;9(4):549-53. doi: 10.1097/JTO.0000000000000094.
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The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer.ALK 抑制剂色瑞替尼克服非小细胞肺癌的克唑替尼耐药性。
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