医学
表皮生长因子受体
肺癌
癌症研究
激酶
癌症
表皮生长因子
受体
内科学
肿瘤科
生长因子受体抑制剂
细胞生物学
生物
作者
Kenichi Suda,Isao Murakami,Kazuko Sakai,Kenji Tomizawa,Hiroshi Mizuuchi,Katsuaki Sato,Kazuto Nishio,Tetsuya Mitsudomi
出处
期刊:Lung Cancer
[Elsevier]
日期:2016-01-01
卷期号:91: 36-40
被引量:37
标识
DOI:10.1016/j.lungcan.2015.11.016
摘要
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 EGFR T790M mutation ratio among EGFR-TKI refractory lesions. In analyzing patient outcomes, we found that patients who developed multiple resistance mechanisms had shorter TTF 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.
科研通智能强力驱动
Strongly Powered by AbleSci AI