Clinical response of the novel activating ALK-I1171T mutation in neuroblastoma to the ALK inhibitor ceritinib.
Clinical response of the novel activating ALK-I1171T mutation in neuroblastoma to the ALK inhibitor ceritinib.
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DOI：
10.1101/mcs.a002550
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发表时间：
2018-08
影响因子：
1.8
通讯作者：
Hallberg B
中科院分区：
文献类型：
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作者：
Guan J;Fransson S;Siaw JT;Treis D;Van den Eynden J;Chand D;Umapathy G;Ruuth K;Svenberg P;Wessman S;Shamikh A;Jacobsson H;Gordon L;Stenman J;Svensson PJ;Hansson M;Larsson E;Martinsson T;Palmer RH;Kogner P;Hallberg B
具有间变性淋巴瘤激酶 (ALK) 融合重排的肿瘤，包括非小细胞肺癌和间变性大细胞淋巴瘤，对 ALK 酪氨酸激酶抑制剂 (TKI) 高度敏感，这强调了此类癌症对 ALK 活性成瘾的观点。尽管 ALK 突变与儿童神经母细胞瘤密切相关，但对 ALK TKI 克唑替尼的反应却令人失望。由于缺乏治疗选择，患有范可尼贫血 (FA) 等 DNA 修复缺陷的胚胎肿瘤患者往往预后不良。在这里，我们报告了一名患有潜在 FA 和 ALK 突变高危神经母细胞瘤的儿童，该儿童对 ALK TKI 色瑞替尼的精准治疗反应强烈。常规化疗引起严重的、危及生命的毒性。初始活检的基因组分析发现了种系 FANCA 突变以及新型 ALK-I1171T 变异。根据 PC12 细胞神经突生长和 NIH3T3 转化的测量，ALK-I1171T 产生有效的功能获得突变体。 ALK-I1171T 对各种 ALK TKI 的药理学抑制分析表明，与克唑替尼相比，色瑞替尼对 ALK-I1171T 的抑制作用提高了 11 倍。免疫亲和耦合 LC-MS/MS 磷酸蛋白质组学分析表明，色瑞替尼响应的 ALK 信号传导减少。因此选择色瑞替尼用于该儿童的治疗。色瑞替尼单药治疗耐受性良好，可导致儿茶酚胺标记物正常化和肿瘤缩小。治疗 7.5 个月后，残留的原发肿瘤缩小，通过手术切除，并表现出分化特征以及 Ki67 水平降低。 21个月治疗后的临床随访显示临床完全缓解，包括所有转移部位。因此，色瑞替尼为 ALK 阳性神经母细胞瘤提供了一种可行的治疗选择。
Tumors with anaplastic lymphoma kinase (ALK) fusion rearrangements, including non-small-cell lung cancer and anaplastic large cell lymphoma, are highly sensitive to ALK tyrosine kinase inhibitors (TKIs), underscoring the notion that such cancers are addicted to ALK activity. Although mutations in ALK are heavily implicated in childhood neuroblastoma, response to the ALK TKI crizotinib has been disappointing. Embryonal tumors in patients with DNA repair defects such as Fanconi anemia (FA) often have a poor prognosis, because of lack of therapeutic options. Here we report a child with underlying FA and ALK mutant high-risk neuroblastoma responding strongly to precision therapy with the ALK TKI ceritinib. Conventional chemotherapy treatment caused severe, life-threatening toxicity. Genomic analysis of the initial biopsy identified germline FANCA mutations as well as a novel ALK-I1171T variant. ALK-I1171T generates a potent gain-of-function mutant, as measured in PC12 cell neurite outgrowth and NIH3T3 transformation. Pharmacological inhibition profiling of ALK-I1171T in response to various ALK TKIs identified an 11-fold improved inhibition of ALK-I1171T with ceritinib when compared with crizotinib. Immunoaffinity-coupled LC-MS/MS phosphoproteomics analysis indicated a decrease in ALK signaling in response to ceritinib. Ceritinib was therefore selected for treatment in this child. Monotherapy with ceritinib was well tolerated and resulted in normalized catecholamine markers and tumor shrinkage. After 7.5 mo treatment, the residual primary tumor shrunk, was surgically removed, and exhibited hallmarks of differentiation together with reduced Ki67 levels. Clinical follow-up after 21 mo treatment revealed complete clinical remission including all metastatic sites. Therefore, ceritinib presents a viable therapeutic option for ALK-positive neuroblastoma.