Anaplastic Lymphoma Kinase Mutation (ALK F1174C) in Small Cell Carcinoma of the Prostate and Molecular Response to Alectinib.
Anaplastic Lymphoma Kinase Mutation (ALK F1174C) in Small Cell Carcinoma of the Prostate and Molecular Response to Alectinib.
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DOI：
10.1158/1078-0432.ccr-18-0332
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发表时间：
2018-06-15
期刊：
影响因子：
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通讯作者：
Abdulkadir SA
中科院分区：
文献类型：
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作者：
Carneiro BA;Pamarthy S;Shah AN;Sagar V;Unno K;Han H;Yang XJ;Costa RB;Nagy RJ;Lanman RB;Kuzel TM;Ross JS;Gay L;Elvin JA;Ali SM;Cristofanilli M;Chae YK;Giles FJ;Abdulkadir SA
前列腺小细胞癌（SCCP）是一种侵袭性疾病，可由前列腺腺癌的新生或转分化引起。间变性淋巴瘤激酶（ALK）基因的改变与神经母细胞瘤、肺癌和其他恶性肿瘤有关，但其在SCCP中的作用尚未有文献记载。我们描述了一位患有ALK F1174C激活突变的难治性新发SCCP患者，他从ALK抑制剂治疗中获得了临床益处。采用新一代测序（NGS）分析原发和循环肿瘤DNA （ctDNA）。在前列腺癌数据库中查询ALK基因、mRNA的改变及其对临床结果的影响。通过慢病毒介导的ALK和ALK F1174C的表达生成体外前列腺细胞系/类器官模型，并评估对ALK抑制剂克唑替尼和阿勒替尼的反应。39岁难治性SSCP患者的原发肿瘤和ctDNA的NGS分析发现ALK F1174C突变。用第二代ALK抑制剂alectinib治疗后，病情在放射学上稳定了6个月以上，症状得到改善，ctDNA等位基因分数下降反映了显著的分子反应。对前列腺癌数据集的分析显示，ALK扩增与预后不良相关。在前列腺癌细胞和类器官中，ALK F1174C的表达可促进生长并诱导神经内分泌标志物神经元特异性烯醇化酶的表达。在抑制表达ALK f1174c的细胞生长方面，阿勒替尼比克唑替尼更有效。这些发现暗示了ALK激活突变在SCCP发病机制中的作用，并提示针对一些SCCP患者的ALK分子改变的治疗潜力。
Small cell carcinoma of the prostate (SCCP) is an aggressive disease that can arise de novo or by transdifferentiation from prostate adenocarcinoma. Alterations in anaplastic lymphoma kinase (ALK) gene are involved in neuroblastoma, lung cancer, and other malignancies but its role in SCCP has not been documented. We describe a patient with refractory de novo SCCP with ALK F1174C activating mutation who obtained clinical benefit from treatment with ALK inhibitor. Next-generation sequencing (NGS) was used to analyze primary and circulating tumor DNA (ctDNA). Prostate cancer databases were queried for alterations in ALK gene, mRNA and its impact in clinical outcomes. In vitro prostate cell line/organoid models were generated by lentiviral-mediated expression of ALK and ALK F1174C and assessed for response to ALK inhibitors crizotinib and alectinib. NGS analysis of the primary tumor and ctDNA of a 39-year old patient with refractory SSCP identified ALK F1174C mutation. Treatment with second-generation ALK inhibitor alectinib resulted in radiographic stable disease for over 6 months, symptomatic improvement, and significant molecular response as reflected by declining ctDNA allele fraction. Analysis of prostate cancer datasets showed that ALK amplification was associated with poor outcome. In prostate cancer cells and organoids, ALK F1174C expression enhanced growth and induced expression of the neuroendocrine marker neuron specific enolase. Alectinib was more effective than crizotinib in inhibiting ALK F1174C-expressing cell growth. These findings implicate ALK activating mutations in SCCP pathogenesis and suggest the therapeutic potential of targeting ALK molecular alterations in some patients with SCCP.