Two novel ALK mutations mediate acquired resistance to the next-generation ALK inhibitor alectinib.
Two novel ALK mutations mediate acquired resistance to the next-generation ALK inhibitor alectinib.
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DOI：
10.1158/1078-0432.ccr-14-1511
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发表时间：
2014-11-15
期刊：
影响因子：
--
通讯作者：
Shaw AT
中科院分区：
文献类型：
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作者：
Katayama R;Friboulet L;Koike S;Lockerman EL;Khan TM;Gainor JF;Iafrate AJ;Takeuchi K;Taiji M;Okuno Y;Fujita N;Engelman JA;Shaw AT
第一代ALK酪氨酸激酶抑制剂（TKI）克唑替尼是ALK重排NSCLC患者的标准治疗药物。几个下一代ALK-TKIs已经进入临床，并在克唑替尼耐药患者中显示出有希望的活性。由于患者即使使用这些下一代ALK-TKIs仍会复发，我们研究了对下一代ALK-TKI alectinib的耐药机制和克服这种耐药的潜在策略。我们建立了阿勒替尼耐药细胞系模型，并分析了阿勒替尼复发患者的耐药肿瘤标本。我们开发了含有alectinib耐药ALK突变的Ba/F3模型，并在这些模型中评估了其他下一代ALK- tkis的效力。我们测试了下一代ALK-TKI ceritinib在获得性耐药患者中的抗肿瘤活性。为了阐明ALK突变的结构-活性-关系，我们使用MP-CAFEE进行了计算热力学模拟。我们从细胞系模型中鉴定出一种新的V1180L看门人突变，从对alectinib产生耐药性的患者中鉴定出第二种新的I1171T突变。这两种ALK突变都对alectinib和crizotinib产生耐药性，但对ceritinib和其他下一代ALK- tkis敏感。用塞瑞替尼治疗患者产生了显著的反应。热力学模拟表明，这两种突变导致不同的结构改变，降低了与alectinib的结合亲和力。我们已经确定了两种新的ALK突变在alectinib暴露后产生，它们对其他下一代ALK- tkis敏感。ceritinib克服alectinib耐药突变的能力表明，使用多种下一代ALK-TKIs进行序贯治疗具有潜在作用。
The first-generation ALK tyrosine kinase inhibitor (TKI) crizotinib is a standard therapy for patients with ALK-rearranged NSCLC. Several next-generation ALK-TKIs have entered the clinic and have shown promising activity in crizotinib-resistant patients. As patients still relapse even on these next-generation ALK-TKIs, we examined mechanisms of resistance to the next-generation ALK-TKI alectinib and potential strategies to overcome this resistance. We established a cell line model of alectinib resistance, and analyzed a resistant tumor specimen from a patient who had relapsed on alectinib. We developed Ba/F3 models harboring alectinib-resistant ALK mutations and evaluated the potency of other next-generation ALK-TKIs in these models. We tested the antitumor activity of the next-generation ALK-TKI ceritinib in the patient with acquired resistance to alectinib. To elucidate structure-activity-relationships of ALK mutations, we performed computational thermodynamic simulation with MP-CAFEE. We identified a novel V1180L gatekeeper mutation from the cell line model and a second novel I1171T mutation from the patient who developed resistance to alectinib. Both ALK mutations conferred resistance to alectinib as well as to crizotinib, but were sensitive to ceritinib and other next-generation ALK-TKIs. Treatment of the patient with ceritinib led to a marked response. Thermodynamics simulation suggests that both mutations lead to distinct structural alterations that decrease the binding affinity with alectinib. We have identified two novel ALK mutations arising after alectinib exposure which are sensitive to other next generation ALK-TKIs. The ability of ceritinib to overcome alectinib-resistance mutations suggests a potential role for sequential therapy with multiple next-generation ALK-TKIs.