Ou Sai-Hong, Milliken Jeffrey C, Azada Michele C, Miller Vincent A, Ali Siraj M, Klempner Samuel J
Department of Medicine, Division of Hematology-Oncology, University of California Irvine School of Medicine, Orange, CA 92868, USA; Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, Orange, CA 92868, USA.
Department of Surgery, Division of Cardiothoracic Surgery, University of California Irvine School of Medicine, Orange, CA 92868, USA.
Lung Cancer. 2016 Jan;91:70-2. doi: 10.1016/j.lungcan.2015.09.006. Epub 2015 Sep 12.
Many acquired resistant mutations to the anaplastic lymphoma kinase (ALK) gene have been identified during treatment of ALK-rearranged non-small cell lung cancer (NSCLC) patients with crizotinib, ceritinib, and alectinib. These various acquired resistant ALK mutations confer differential sensitivities to various ALK inhibitors and may provide guidance on how to sequence the use of many of the second generation ALK inhibitors. We described a patient who developed an acquired ALK F1174V resistant mutation on progression from crizotinib that responded to alectinib for 18 months but then developed an acquired ALK I1171S mutation to alectinib. Both tumor samples had essentially the same genomic profile by comprehensive genomic profiling otherwise. This is the first patient report that demonstrates ALK F1174V mutation is sensitive to alectinib and further confirms missense acquired ALK I1171 mutation is resistant to alectinib. Sequential tumor re-biopsy for comprehensive genomic profiling (CGP) is important to appreciate the selective pressure during treatment with various ALK inhibitors underpinning the evolution of the disease course of ALK+NSCLC patients while on treatment with the various ALK inhibitors. This approach will likely help inform the optimal sequencing strategy as more ALK inhibitors become available. This case report also validates the importance of developing structurally distinct ALK inhibitors for clinical use to overcome non-cross resistant ALK mutations.
在使用克唑替尼、色瑞替尼和阿来替尼治疗间变性淋巴瘤激酶（ALK）重排的非小细胞肺癌（NSCLC）患者的过程中，已发现许多对ALK基因的获得性耐药突变。这些各种获得性耐药的ALK突变对各种ALK抑制剂具有不同的敏感性，并可能为如何安排多种第二代ALK抑制剂的使用顺序提供指导。我们描述了一名患者，该患者在克唑替尼治疗进展过程中出现了获得性ALK F1174V耐药突变，对阿来替尼有18个月的反应，但随后又出现了对阿来替尼的获得性ALK I1171S突变。否则，通过全面基因组分析，两个肿瘤样本的基因组图谱基本相同。这是第一例证明ALK F1174V突变对阿来替尼敏感，并进一步证实错义获得性ALK I1171突变对阿来替尼耐药的患者报告。在ALK + NSCLC患者接受各种ALK抑制剂治疗期间，进行连续肿瘤再活检以进行全面基因组分析（CGP），对于了解治疗过程中的选择性压力很重要，这种压力支撑着疾病进程的演变。随着更多ALK抑制剂问世，这种方法可能有助于确定最佳的用药顺序策略。本病例报告还验证了开发结构不同的ALK抑制剂用于临床以克服非交叉耐药ALK突变的重要性。
