*Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, Orange, California; †Division of Hematology Oncology, Department of Medicine, University of California Irvine School of Medicine, Orange, California; ‡Division of Surgical Oncology, Department of Surgery, University of California Irvine School of Medicine, Orange, California; §Division of Nuclear Medicine, Department of Radiology, University of California Irvine Medical Center, University of California Irvine School of Medicine, Orange, California; and ‖Foundation Medicine Inc, Cambridge, Massachusetts.
J Thorac Oncol. 2014 Apr;9(4):549-53. doi: 10.1097/JTO.0000000000000094.
Acquired secondary mutations in the anaplastic lymphoma kinase (ALK) gene have been identified in ALK-rearranged (ALK+) non-small-cell lung cancer (NSCLC) patients who developed disease progression while on crizotinib treatment. Here, we identified a novel secondary acquired NSCLC ALK F1174V mutation by comprehensive next-generation sequencing in one ALK+ NSCLC patient who progressed on crizotinib after a prolonged partial response to crizotinib. In a second case, we identified a secondary acquired ALK G1202R, which also confers resistance to alectinib (CH5424802/RO5424802), a second-generation ALK inhibitor that can inhibit ALK gatekeeper L1196M mutation in vitro. ALK G1202R is located at the solvent front of the ALK kinase domain and exhibits a high level of resistance to all other ALK inhibitors currently in clinical development in vitro. Comprehensive genomic profiling of resistant tumor is increasingly important in tailoring treatment decisions after disease progression on crizotinib in ALK+ NSCLC given the promise of second-generation ALK inhibitors and other therapeutic strategies.
在接受克唑替尼治疗后出现疾病进展的 ALK 重排（ALK+）非小细胞肺癌（NSCLC）患者中，已经鉴定出间变性淋巴瘤激酶（ALK）基因的获得性继发性突变。在这里，我们通过对一名接受克唑替尼治疗后长时间部分缓解后进展的 ALK+ NSCLC 患者进行全面的下一代测序，鉴定出了一种新型的获得性 NSCLC ALK F1174V 突变。在第二种情况下，我们鉴定出一种继发性获得性 ALK G1202R，它也对第二代 ALK 抑制剂艾乐替尼（CH5424802/RO5424802）产生耐药性，该抑制剂可在体外抑制 ALK 门控 L1196M 突变。ALK G1202R 位于 ALK 激酶结构域的溶剂前沿，在体外对所有其他目前处于临床开发阶段的 ALK 抑制剂均表现出高度耐药性。鉴于第二代 ALK 抑制剂和其他治疗策略的前景，在 ALK+ NSCLC 患者接受克唑替尼治疗后疾病进展时，对耐药肿瘤进行全面的基因组分析对于制定治疗决策越来越重要。
