Elucidation of Resistance Mechanisms to Second-Generation ALK Inhibitors Alectinib and Ceritinib in Non-Small Cell Lung Cancer Cells.
Elucidation of Resistance Mechanisms to Second-Generation ALK Inhibitors Alectinib and Ceritinib in Non-Small Cell Lung Cancer Cells.
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DOI：
10.1016/j.neo.2016.02.001
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发表时间：
2016-03
期刊：
影响因子：
--
通讯作者：
Wang S
中科院分区：
文献类型：
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作者：
Dong X;Fernandez-Salas E;Li E;Wang S
克唑替尼是第一个被批准用于治疗携带ALK融合基因的非小细胞肺癌（NSCLC）的间变性淋巴瘤激酶（ALK）抑制剂，但在临床上发现，Alectinib和ceritinib是第二代ALK抑制剂，在克唑替尼初治和克唑替尼治疗中均显示出显著的临床应答。携带ALK融合基因的耐药NSCLC患者。尽管它们的活性令人印象深刻，但也出现了对alectinib和ceritinib的临床耐药性。在本研究中，我们在体外阐明了携带EML 4-ALK变体1融合的H3122 NSCLC细胞系对这些第二代ALK抑制剂的耐药机制。用alectinib和ceritinib延长亲代H3122细胞的处理导致两种细胞系对alectinib和ceritinib的敏感性比亲代H3122细胞系低10倍。尽管ALK激酶结构域突变是克唑替尼的常见耐药机制，但我们在这些耐药细胞系中未检测到任何ALK突变。相反，在两种耐药细胞系中均观察到磷酸化ALK和替代受体酪氨酸激酶（如磷酸化EGFR、磷酸化HER 3和磷酸化IGFR-1 R）过表达。此外，NRG 1是HER 3的配体，通过NRG 1-HER 3-EGFR轴激活EGFR家族途径而上调并导致耐药。与EGFR抑制剂（特别是阿法替尼）联合治疗可有效克服耐药性。我们的研究为第二代ALK抑制剂的适应性耐药提供了新的机制见解，并提出了在NSCLC中对抗这些第二代ALK抑制剂耐药的潜在临床策略。
Crizotinib is the first anaplastic lymphoma kinase (ALK) inhibitor to have been approved for the treatment of non–small cell lung cancer (NSCLC) harboring an ALK fusion gene, but it has been found that, in the clinic, patients develop resistance to it. Alectinib and ceritinib are second-generation ALK inhibitors which show remarkable clinical responses in both crizotinib-naive and crizotinib-resistant NSCLC patients harboring an ALK fusion gene. Despite their impressive activity, clinical resistance to alectinib and ceritinib has also emerged. In the current study, we elucidated the resistance mechanisms to these second-generation ALK inhibitors in the H3122 NSCLC cell line harboring the EML4-ALK variant 1 fusion in vitro. Prolonged treatment of the parental H3122 cells with alectinib and ceritinib led to two cell lines which are 10 times less sensitive to alectinib and ceritinib than the parental H3122 cell line. Although mutations of ALK in its kinase domain are a common resistance mechanism for crizotinib, we did not detect any ALK mutation in these resistant cell lines. Rather, overexpression of phospho-ALK and alternative receptor tyrosine kinases such as phospho-EGFR, phospho-HER3, and phospho-IGFR-1R was observed in both resistant cell lines. Additionally, NRG1, a ligand for HER3, is upregulated and responsible for resistance by activating the EGFR family pathways through the NRG1-HER3-EGFR axis. Combination treatment with EGFR inhibitors, in particular afatinib, was shown to be effective at overcoming resistance. Our study provides new mechanistic insights into adaptive resistance to second-generation ALK inhibitors and suggests a potential clinical strategy to combat resistance to these second-generation ALK inhibitors in NSCLC.