<i>ALK</i>重排晚期非小细胞肺癌对克唑替尼耐药的分子特征

邓秋梅; 王涵敏; 康劲; 杨衿记

doi:10.12019/j.issn.1671-5144.2021.02.010

ALK重排晚期非小细胞肺癌对克唑替尼耐药的分子特征

广东省心血管病研究所, 广东省人民医院、广东省医学科学院, 广东省肺癌研究所,广东省肺癌转化医学重点实验室, 广州 510080

基金项目: 广东省人民医院登峰计划（DFJH201809）; 国家自然科学基金项目（81972164）; 广东省自然科学基金资助项目（2019A1515010931）; 国家科技部国家重点技术研发计划; 重大非传染性疾病防控资助项目（2016YFC1303304）; 广东省科技厅重点实验室系统项目——广东省肺癌转化医学重点实验室（2017B030314120）

详细信息

作者简介:
邓秋梅（1994-）,女,广东清远人,硕士研究生,主要研究方向为肺癌的靶向治疗。

通讯作者:
杨衿记, Tel: 020-81884713-80412, E-mail: yangjinji@gdph.org.cn。

中图分类号: R734.2
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出版历程
- 收稿日期: 2021-04-22
- 发布日期: 2021-04-27

Molecular Features of Resistance to Crizotinib in Advanced Non-Small-Cell Lung Cancer With ALK Rearrangement

Guangdong Cardiovascular Institute, Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China

摘要

摘要: 目的间变性淋巴瘤激酶（anaplastic lymphoma kinase,ALK）融合基因是非小细胞肺癌（non-small-cell lung cancer,NSCLC）一个重要亚型,靶向ALK的酪氨酸激酶抑制剂（tyrosine kinase inhibitor,TKI）显著改善了这一类患者的临床治疗结局。遗憾的是,大部分患者经过一段时间的ALK-TKI治疗之后终会产生耐药。研究发现其主要耐药机制包括ALK继发性耐药突变、ALK基因扩增、旁路及下游通路激活等。本研究旨在探讨ALK-TKI克唑替尼耐药的分子特征。方法我们回顾性收集了广东省肺癌研究所从2016年1月到2020年12月通过Ventana免疫组化（immunohistochemistry,IHC）、荧光原位杂交技术（fluorescence in situ hybridization,FISH）、组织或液体二代测序（next-generation sequencing,NGS）确诊为ALK重排晚期NSCLC患者共234例。对耐药后的组织/体液进行NGS检测,以分析克唑替尼耐药的分子特征。使用Fisher's精确检验分析ALK融合变体与G1202R的关系并结合临床资料进行生存分析。结果我们总共筛选出44例使用克唑替尼治疗的晚期ALK重排NSCLC患者,并且在疾病进展后进行了至少1次重复活检（包括31个血浆标本和39个组织标本）。棘皮动物微管样蛋白4-间变淋巴瘤激酶（echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase,EML4-ALK）变异体3（v3）是本队列中最常见的ALK变体,其次为EML4-ALK变体1（v1）。与其他变体相比,v3变体的人群中在克唑替尼耐药后更容易出现ALK G1202R耐药突变（0% vs. 38%,P=0.006 4）。在这44例患者中有21例（48%）发现了ALK酪氨酸激酶区域的第二位点突变,其中L1196M占比最多,占13%,其次为两个以上ALK突变（11%）和G1202R（7%）。生存分析显示v3与其他变体的两组人群使用克唑替尼治疗的中位无进展生存期（progression-free survival,PFS）均为8.8个月,差异无统计学意义（P=0.683 6）。根据耐药后有无ALK耐药突变进行生存分析,ALK耐药突变组的人群使用克唑替尼治疗的中位PFS为6.6个月,无突变组则为8.8个月,差异无统计学意义（P=0.615 0）。结论晚期ALK重排NSCLC患者克唑替尼耐药后以ALK激酶区域突变为主。v3变体克唑替尼耐药后更容易产生ALK G1202R耐药突变。
- 非小细胞肺癌 /
- ALK重排 /
- 克唑替尼 /
- 耐药机制
Abstract: Objective The anaplastic lymphoma kinase （ALK） fusion was an important driver gene of non-small-cell lung cancer （NSCLC）, and ALK-tyrosine kinase inhibitor （TKI） have significantly improved clinical outcomes in patients with ALK fusion. Unfortunately, resistance to ALK-TKI inevitably occurs after a period of treatment. The main mechanisms of resistance have been found to include ALK secondary resistance mutations, ALK gene amplification, bypass and downstream pathway activation. The aim of this study was to investigate the mechanism of resistance to crizotinib in clinical practice. Methods We retrospectively collected a total of 234 patients with ALK-positive advanced NSCLC from January 2016 to December 2020 at Guangdong Lung Cancer Institute. Ventana immunohistochemistry （IHC）, fluorescence in situ hybridization （FISH）, tissue or liquid next-generation sequencing （NGS） were conducted to confirm ALK rearrangement. Tissues / plasma based NGS was performed again after ALK-TKI resistance. Clinicopathological and molecular characteristics and clinical data were collected for Kaplan Meier analysis. Results We screened a total of 44 patients with advanced ALK-rearranged NSCLC treated with crizotinib and who underwent at least 1 repeat biopsy （including 31 plasma specimens and 39 tissue specimens） after disease progression. Echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase （EML4-ALK） variant 3 （v3） was the most common ALK variant in this cohort, followed by EML4-ALK variant 1 （v1）. Of these variants, v3 cohort was more likely to developed ALK G1202R resistance mutation after crizotinib resistance compared to the other variants （0% vs. 38%, P=0.006 4）. A second site mutation resistance mechanism in the ALK tyrosine kinase region was identified in 21 of these 44 patients （48%）, with L1196M accounting for the most （13%）, followed by more than 2 ALK mutations （11%） and G1202R （7%）. Survival analysis showed that the progression-free survival （PFS） of v3 and other variants groups treated with crizotinib were both 8.8 months, with no statistically significant difference （P=0.683 6）. Survival analysis based on the presence or absence of ALK resistance mutation after drug resistance showed that PFS was 6.6 months in the ALK resistance mutation group, and 8.8 months in the absence of ALK resistance mutation group, with no statistically significant difference （P=0.615 0）. Conclusions ALK kinase domain mutations predominate after crizotinib resistance in patients with advanced ALK rearranged NSCLC. EML4-ALK v3 variants were more likely to produce ALK G1202R resistance mutations after crizotinib resistance.
- non-small cell lung cancer /
- ALK rearrangement /
- crizotinib /
- resistance mechanism

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参考文献(17)

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