Resistance profiles of anaplastic lymphoma kinase tyrosine kinase inhibitors in advanced non-small-cell lung cancer: a multicenter study using targeted next- generation sequencing
Resistance profiles of anaplastic lymphoma kinase tyrosine kinase inhibitors in advanced non-small-cell lung cancer: a multicenter study using targeted next- generation sequencing
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DOI：
10.1016/j.ejca.2021.06.043
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发表时间：
2021-08-13
影响因子：
8.4
通讯作者：
Shih, Jin-Yuan
中科院分区：
文献类型：
--
作者：
Lin, Yen-Ting;Chiang, Chi-Lu;Shih, Jin-Yuan
简介：间变性淋巴瘤激酶（ALK）酪氨酸激酶抑制剂（TKI）克唑替尼、塞瑞替尼、阿来替尼、brigatinib和劳拉替尼获批用于治疗伴有ALK重排的晚期非小细胞肺癌（NSCLC）。方法：这项前瞻性多中心研究分析了ALK TKI治疗进展后NSCLC患者的游离DNA（cfDNA）和/或癌组织，使用靶向下一代测序技术。结果：共入组88例患者，分析了31例癌组织和90份cfDNA样本。在32例克唑替尼耐药癌症中发现了5种（16%）ALK突变（L1196 M x 2、I1171 T、D1203 N、G1269 A/F1174 L）和3种可能的旁路突变（NRAS G12 V、EGFR R108 K、PIK 3CA E545 K）。在18例色瑞替尼耐药癌症中发现了4种（22%）ALK突变（G1128 A、G1202 R、G1269 A、I1171 T/E1210 K）和3种可能的旁路突变（KIT D820 E、MET E1012*、EGFR P265_C291 del）。在24例阿来替尼耐药癌症中发现了4例（17%）ALK突变（G1202 R x 2、W1295 C、G1202 R/L1196 M）和1例可能的旁路突变（EGFR P753 S）。在18例劳拉替尼耐药癌症中发现了2例（11%）ALK突变（G1202 R/G1269 A x 2）和2例可能的旁路突变（BRAF V600 E、MET D1246 N）。在同时配对组织和cfDNA样本的患者中（n = 20），分别在9例（45%）和6例（30%）病例中发现突变;一致率为45%。结论：ALK TKI耐药的机制是异质性的;在不到三分之一的患者中发现ALK突变。克唑替尼、塞瑞替尼和阿来替尼耐药肺癌中可能发生可导致劳拉替尼耐药的ALK复合突变。(C)2021作者（S）爱思唯尔有限公司出版
Introduction: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are approved for advanced non-small-cell lung cancer (NSCLC) with ALK rearrangement. However, the mechanisms of resistance remain largely unclear.Methods: This prospective multicenter study analyzed cell-free DNA (cfDNA) and/or cancer tissues of patients with NSCLC after progression on ALK TKI(s), using targeted next generation sequencing. Patients' clinicopathologic characteristics and treatment outcomes were analyzed.Results: Overall, 88 patients were enrolled; 31 cancer tissues and 90 cfDNA samples were analyzed. Five (16%) ALK mutations (L1196M x 2, I1171T, D1203N, G1269A/F1174L) and 3 possible bypass mutations (NRAS G12V, EGFR R108K, PIK3CA E545K) were found in 32 crizotinib-resistant cancers. Four (22%) ALK mutations (G1128A, G1202R, G1269A, I1171T/E1210K) and 3 possible bypass mutations (KIT D820E, MET E1012*, EGFR P265_C291del) were found in 18 ceritinib-resistant cancers. Four (17%) ALK mutations (G1202R x 2, W1295C, G1202R/L1196M) and 1 possible bypass mutation (EGFR P753S) were found in 24 alectinib-resistant cancers. Two (11%) ALK mutations (G1202R/G1269A x 2) and 2 possible bypass mutations (BRAF V600E, MET D1246N) were found in 18 lorlatinib-resistant cancers. In patients with simultaneous paired tissue and cfDNA samples (n = 20), mutations were identified in 9 (45%) and 6 (30%) cases, respectively; the concordance rate was 45%.Conclusions: The mechanisms of ALK TKI resistance were heterogeneous; ALK mutations were found in less than one-third of patients. Compound ALK mutations, which may confer lorlatinib resistance, may occur in crizotinib, ceritinib, and alectinib-resistant lung cancers. (C) 2021 The Author(s). Published by Elsevier Ltd.