Research progress on drug resistance mechanism and management of targeted therapy for ALK-positive non-small cell lung cancer
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摘要: 目前，肺癌仍是世界上最常见的恶性肿瘤，位居癌症死亡原因的第1位，随着靶向治疗的发展，死亡率已显著降低。间变性淋巴瘤激酶（anaplastic lymphoma kinase，ALK）作为对治疗有显著反应的非小细胞肺癌（non-small cell lung carcinoma，NSCLC）基因型，发展至今已有三代针对其靶位的间变性淋巴瘤激酶酪氨酸激酶抑制剂（anaplastic lymphoma kinase-tyrosine kinase inhibitors，ALK-TKIs），新一代的ALK-TKIs比上一代具有更为广泛的作用位点覆盖范围及更强的药物组织穿透能力。发展前路可观，但仍无法规避耐药问题，随着多种ALK抑制剂应用及联合治疗的选择增多，新的耐药后突变、复合突变以及其他多种耐药机制已逐渐被关注。与此同时，相关早期诊断及预后标志物也被发掘证实。NSCLC耐药机制及检测手段在不断更新，治疗以基于基因依赖性的个体化治疗为主，以期通过对多种耐药方式的介入，使得NSCLC逐渐转变为慢性病。本文归纳介绍了ALK抑制剂应用于NSCLC的现状及耐药机制，耐药后治疗策略及诊断和预后标志物的进展，旨在为ALK阳性NSCLC的诊治及耐药后管理策略提供参考依据。Abstract: Lung cancer is the most common malignant tumor worldwide, meanwhile the first cause of cancer-related deaths currently. Fortunately targeted therapy have dramatically reduced lung cancer-related mortality. As part of the genotype that displays significant association with non-small cell lung carcinoma (NSCLC), the anaplastic lymphoma kinase (ALK) gene has been developed three generations of anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs). Each generation of ALK-TKIs exhibits wider coverage of target sites and stronger tissue penetration ability than the previous. Despite considerable effort made through ALK-TKIs, drug resistance cannot be avoid. With increasing application of multiple ALK inhibitors and combined treatment regimens, new drug resistance mutations, compound mutations, and other mechanisms underlying drug resistance have been reported. Simultaneously, new markers for early diagnosis as well as predicting prognosis have also been identified. In order to get better understanding of drug resistance mechanisms and improved methods to detect NSCLC, the treatment become personalized based on genetic information certainly. It is hoped that newly discovered means to overcome drug resistance will place NSCLC in the category of chronic diseases near future. This review summarizes the research studies on ALK gene, drug resistance mechanisms and treatment strategies progress of targeted therapy, availability of diagnostic and prognostic markers to provide novel insights for the clinical management of ALK positive NSCLC patients.
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表 1 ALK-TKIs相关作用靶点及耐药突变
TKI 有效靶点 敏感突变 耐药突变 是否抗L1196M\C1156Y\G1202R 透过血脑屏障 crizotinib[5-6] ALK、ROS1、
METL1198F 1151Tins、C1156Y/T、L1196M、G1202R、G1269A/S、G1128A、L1152P/R、E1210K、I1171T/N/S、F1245V、F1174V/L/C、V1180L、D1203N、S1206C/Y 否\否\否 否 ceritinib[7-8] ALK、ROS1、IGF1R、InsR L1196M、G1269A、I1171T、S1206Y、V1180L C1156Y/T、D1203N、I1151Tins、G1202R、F1174C/V、L1198F、L1152P/R、G1123S 是\否\否 是 alectinib[9-10] ALK、RET L1196M、S1206Y、G1269A、C1156Y、F1174L、1151Tins、L1152R I1171T/N/S、V1180L、G1202R 是\是\是 是 brigatinib[11-12] ALK、ROS1、EGFR-T790M L1196M、C1156Y、G1269A、S1206Y、L1152R、F1174C、1151Tins、I1171T、D1203N、E1210K、F1245C G1202R、S1206C/F、F1174V+L1198F 是\是\否 是 lorlatinib[13-14] ALK、ROS1 G1202R、G1269A、F1174L、S1206Y、I1171T、E1210K、L1152R 、1151Tins、V1180L、D1203N L1198F 是\是\是 是 ensartinib[9,15] ALK、ROS1、MET、AXL、ABL、EphA2、
LTK、SLKF1174、C1156Y、L1196M、S1206R、T1151、G1202R G1269A、E1210K 是\是\是 是 entrectinib[16-17] ALK、ROS1、PAN-TRK G1269A、C1156Y、L1196M NA 是\是\未知 是 
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