Heterogeneity in resistance mechanisms causes shorter duration of epidermal growth factor receptor kinase inhibitor treatment in lung cancer
Heterogeneity in resistance mechanisms causes shorter duration of epidermal growth factor receptor kinase inhibitor treatment in lung cancer
复制标题
DOI：
10.1016/j.lungcan.2015.11.016
复制
发表时间：
2016-01-01
期刊：
影响因子：
5.3
通讯作者：
Mitsudomi, Tetsuya
中科院分区：
文献类型：
--
作者：
Suda, Kenichi;Murakami, Isao;Mitsudomi, Tetsuya
目的：表皮生长因子受体（EGFR）-酪氨酸激酶抑制剂（TKI）被用作携带体细胞EGFR突变的转移性肺癌的一线治疗。然而，获得对这些药物的耐药性几乎是不可避免的。T790 M（EGFR基因的密码子790处的苏氨酸至甲硫氨酸的取代）和MET扩增是众所周知的耐药机制，并且我们先前通过分析T790 M和MET基因拷贝数证明了六名尸检患者中的三名显示出耐药机制的肿瘤间异质性（苏达等人，2010年）。为了进一步阐明异质性在获得性耐药中的作用，在这里，我们进行了进一步的分析，包括额外的five patients.Materials和方法：我们分析了体细胞突变50癌症相关基因的26 EGFR-TKI难治性病变从四个尸检患者使用靶向测序。通过实时PCR分析MET和ERBB 2拷贝数。从我们最近的研究中获得了另外一名患者的数据（苏达等人，2015年）的报告。结果和结论：我们在分析的四名患者中的两名中观察到耐药机制的异质性（T790 M + MET基因拷贝数增加，和突变型EGFR丢失+未知）。我们还确定了EGFR-TKI难治性病变中埃格T790 M突变率的定量异质性。在分析患者结局时，我们发现，与发生单一耐药机制的患者相比，发生多种耐药机制的患者TIT较短（p = 0.022）。EGFR-TKI治疗失败后的PPS在这两组之间相容（p=0.42）。这些发现进一步加深了我们对EGFR-TKI获得性耐药机制的理解，并可能导致EGFR突变肺癌患者对第一代EGFR-TKI获得性耐药后更好的治疗策略。(C)2015爱思唯尔爱尔兰有限公司版权所有。
Objectives: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are used as a first line therapy for metastatic lung cancer harboring somatic EGFR mutation. However, acquisition of resistance to these drugs is almost inevitable. T790M (threonine to methionine substitution at codon 790 of the EGFR gene) and MET amplification are well-known resistance mechanisms, and we previously demonstrated that three of six autopsied patients showed inter-tumor heterogeneity in resistance mechanisms by analyzing T790M and MET gene copy number (Suda et al., 2010). To further elucidate the role of heterogeneity in acquired resistance, here we performed further analyses including additional five patients.Materials and methods: We analyzed somatic mutations in 50 cancer-related genes for 26 EGFR-TKI refractory lesions from four autopsied patients using target sequencing. MET and ERBB2 copy numbers were analyzed by real-time PCR. Data for additional one patient was obtained from our recent study (Suda et al., 2015). Relationship between heterogeneity in resistance mechanism(s) and time to treatment failure (TTF) of EGFR-TKI and post-progression survival (PPS) were analyzed.Results and conclusion: We observed heterogeneity of resistance mechanisms in two of four patients analyzed (T790M + MET gene copy number gain, and mutant EGFR loss + unknown). We also identified quantitative heterogeneity in EGER T790M mutation ratio among EGFR-TKI refractory lesions. In analyzing patient outcomes, we found that patients who developed multiple resistance mechanisms had shorter TIT compared with those who developed single resistance mechanism (p = 0.022). PPS after EGFR-TKI treatment failure was compatible between these two groups (p=0.42). These findings further our understanding of acquired resistance mechanisms to EGFR-TKIs, and may lead to better treatment strategies after acquisition of resistance to first generation EGFR-TKIs in lung cancer patients with EGFR mutations. (C) 2015 Elsevier Ireland Ltd. All rights reserved.