Crizotinib-Resistant NPM-ALK Mutants Confer Differential Sensitivity to Unrelated Alk Inhibitors
Crizotinib-Resistant NPM-ALK Mutants Confer Differential Sensitivity to Unrelated Alk Inhibitors
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DOI：
10.1158/1541-7786.mcr-12-0569
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发表时间：
2013-02-01
影响因子：
5.2
通讯作者：
Gambacorti-Passerini, Carlo
中科院分区：
文献类型：
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作者：
Ceccon, Monica;Mologni, Luca;Gambacorti-Passerini, Carlo
ALK/MET 双重抑制剂克唑替尼最近被批准用于治疗转移性和晚期 ALK+ NSCLC，目前正在进行其他 ALK 相关疾病的临床试验。正如根据其他酪氨酸激酶抑制剂的临床经验所预测的那样，第一个对克唑替尼产生耐药性的突变已在非小细胞肺癌 (NSCLC) 患者和一名炎性肌纤维母细胞瘤 (IMT) 患者中出现。在这里，我们将注意力集中在间变性大细胞淋巴瘤 (ALCL) 上，其中致癌融合蛋白 NPM-ALK 负责 70% 至 80% 的病例，代表了理想的克唑替尼靶点。我们选择并表征了 2 种人类 NPM-ALK+ ALCL 细胞系 KARPAS-299 和 SUP-M2，它们能够在不同克唑替尼浓度下存活和增殖。 ALK 激酶结构域测序显示，在高克唑替尼剂量下，每个细胞系中的单一突变占主导地位，即分别在 Karpas-299 和 SUP-M2 细胞中的 L1196Q 和 I1171N。这些突变还使表达人 NPM-ALK 的 Ba/F3 细胞对克唑替尼产生耐药性。耐药细胞群以及突变的 Ba/F3 细胞对另外两种 ALK 抑制剂的敏感性进行了表征：双重 ALK/EGFR 抑制剂 AP26113 和 NVP-TAE684。虽然 L1196Q 阳性细胞系对两种抑制剂均敏感，但携带 I1171N 取代的细胞对所有测试的 ALK 抑制剂表现出交叉耐药性。这项研究为克唑替尼治疗后可能复发的 ALCL 患者的治疗提供了潜在的相关信息。摩尔癌症研究中心； 11(2)； 122-32。 (c) 2012 年 AACR。
The dual ALK/MET inhibitor crizotinib was recently approved for the treatment of metastatic and late-stage ALK+ NSCLC, and is currently in clinical trial for other ALK-related diseases. As predicted after other tyrosine kinase inhibitors' clinical experience, the first mutations that confer resistance to crizotinib have been described in patients with non-small cell lung cancer (NSCLC) and in one patient inflammatory myofibroblastic tumor (IMT). Here, we focused our attention on the anaplastic large cell lymphoma (ALCL), where the oncogenic fusion protein NPM-ALK, responsible for 70% to 80% of cases, represents an ideal crizotinib target. We selected and characterized 2 human NPM-ALK+ ALCL cell lines, KARPAS-299 and SUP-M2, able to survive and proliferate at different crizotinib concentrations. Sequencing of ALK kinase domain revealed that a single mutation became predominant at high crizotinib doses in each cell line, namely L1196Q and I1171N in Karpas-299 and SUP-M2 cells, respectively. These mutations also conferred resistance to crizotinib in Ba/F3 cells expressing human NPM-ALK. The resistant cell populations, as well as mutated Ba/F3 cells, were characterized for sensitivity to two additional ALK inhibitors: the dual ALK/EGFR inhibitor AP26113 and NVP-TAE684. While L1196Q-positive cell lines were sensitive to both inhibitors, cells carrying I1171N substitution showed cross-resistance to all ALK inhibitors tested. This study provides potentially relevant information for the management of patients with ALCL that may relapse after crizotinib treatment. Mol Cancer Res; 11(2); 122-32. (c) 2012 AACR.