摘要

Purpose: 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.Experimental Design: 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.Results: 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.Conclusions: These findings implicate ALK-activating mutations in SCCP pathogenesis and suggest the therapeutic potential of targeting ALK molecular alterations in some patients with SCCP. Clin Cancer Res; 24(12); 2732-9. ©2018 AACR.

译文

目的: 前列腺小细胞癌 (SCCP) 是一种侵袭性疾病,可从头开始或通过前列腺腺癌转分化产生。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 中的作用尚未被记录。我们描述了一名患有 ALK F1174C-activating 突变的难治性新生 SCCP 患者,该患者从 ALK 抑制剂治疗中获得了临床益处。实验设计: 使用下一代测序 (NGS) 分析原发性和循环肿瘤 DNA (ctDNA)。有人查询了前列腺癌数据库中 ALK 基因、 mRNA 的改变及其对临床结果的影响。通过 ALK 和 ALK F1174C 的慢病毒介导表达产生体外前列腺细胞系/类器官模型,并评估对 ALK 抑制剂 crizotinib 和 alectinib 的反应。结果: 对一名 39 岁难治性 SSCP 患者的原发性肿瘤和 ctDNA 进行 NGS 分析,发现 ALK F1174C 突变。第二代 ALK 抑制剂 alectinib 治疗导致影像学稳定疾病超过 6 个月,症状改善,并通过降低 ctDNA 等位基因分数反映出显著的分子反应。对前列腺癌数据集的分析表明,ALK 扩增与不良结果相关。在前列腺癌细胞和类器官中,ALK F1174C 表达增强了神经内分泌标记神经元特异性烯醇化酶的生长和诱导表达。阿雷替尼在抑制 ALK F1174C-expressing 细胞生长方面比克唑替尼更有效。结论: 这些发现暗示了 SCCP 发病机制中的 ALK 激活突变,并表明在一些 SCCP 患者中靶向 ALK 分子改变的治疗潜力。Clin Cancer Res; 24 (12); 2732-9。©2018 AACR。

Alectinib

肿瘤 肺癌 药物
概述  :  

阿来替尼也叫艾乐替尼,Alectinib是一种酪氨酸激酶抑制剂靶向作用于ALK和RET。艾乐替尼能够抑制ALK磷酸化和ALK-介导的下游信号蛋白STAT3和AKT的激活,并且抑制ALK融合、扩增等。降低肿瘤细胞的活力,最终促进肿瘤细胞的凋亡。ALK是一种间变性淋巴瘤激酶,在ALK突变的患者中由于染色体结构发生了改变,导致EML4基因与ALK基因的重排,使肿瘤细胞进展。   2015年12月,美国FDA批准罗氏的艾乐替尼上市,用于克唑替尼耐药

Alectinib

释    义   n. 艾乐替尼;阿雷替尼;阿来替尼

例    句   There are currently several ALK inhibitors, including crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib which have been licensed by the US Food and Drug Administration or the European Medicines Agency for the treatment of ALK+ NSCLC patients. 目前有几种ALK抑制剂,包括克唑替尼、色瑞替尼、阿来替尼、布加替尼和劳拉替尼,已经获得美国食品和药物管理局或欧洲药物管理局的许可,用于治疗ALK+非小细胞肺癌患者。

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