Introduction: Lung cancer is the leading cause of cancer‐related deaths worldwide. ALK receptor tyrosine kinase gene (ALK) rearrangement has been identified in 3% to 5% of patients with NSCLC. The most common ALK rearrangement is echinoderm microtubule associated protein like 4 (EML4)‐ALK, with several variants that can be targeted by the tyrosine kinase inhibitor crizotinib. Methods: In this study using comprehensive next‐generation sequencing targeting 416 pan‐cancer genes and introns of 16 genes frequently rearranged in cancer, we identified a novel cut‐like homeobox 1 gene (CUX1)‐ALK fusion gene in a patient with lung adenocarcinoma. The exact CUX1‐ALK fusion transcript was determined by RNA sequencing and confirmed by reverse‐transcriptase polymerase chain reaction. The oncogenic ability of CUX1‐ALK fusion gene was further validated in cells of the line 293T for the activation of anaplastic lymphoma kinase (ALK) self‐phosphorylation and downstream signaling pathways. Results: After detection of the CUX1‐ALK fusion gene, RNA sequencing analysis of formalin‐fixed paraffin‐embedded sections from the primary tumor specimen was applied to reveal a 97‐nucleotide fragment from CUX1 intron 8 inserted before the nucleotide 53 position in ALK exon 20. Expression of the cut‐like homeobox 1–ALK fusion protein in 293T cells confirmed the self‐phosphorylation of the fusion protein and the activation of ALK downstream signaling pathways, including the mitogen‐activated protein kinase, Janus kinase–signal transducer and activator of transcription, and phosphoinositide 3‐kinase/AKT signaling pathways, which could all be inhibited by the addition of crizotinib. Furthermore, the patient showed a superior response to crizotinib, with a progression‐free survival of 20 months. Conclusions: This study provides the novel finding of a CUX1‐ALK fusion gene from a patient with NSCLC that could provide personalized treatment solutions for the maximum benefit to patients with NSCLC.

中文翻译：

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简报：CUX1-ALK，一种在非小细胞肺癌中对克唑替尼有反应的新型 ALK 重排

简介：肺癌是全球癌症相关死亡的主要原因。已在 3% 至 5% 的 NSCLC 患者中发现 ALK 受体酪氨酸激酶基因 (ALK) 重排。最常见的 ALK 重排是棘皮动物微管相关蛋白，如 4 (EML4)-ALK，有几种变体可以被酪氨酸激酶抑制剂克唑替尼靶向。方法：在这项研究中，我们使用针对 416 个泛癌基因和 16 个在癌症中经常重排的基因的内含子进行全面的二代测序，在肺腺癌患者中鉴定了一个新的切割样同源框 1 基因（CUX1）-ALK 融合基因。 . 确切的 CUX1-ALK 融合转录物通过 RNA 测序确定，并通过逆转录酶聚合酶链反应确认。CUX1-ALK 融合基因的致癌能力在 293T 系细胞中得到进一步验证，用于激活间变性淋巴瘤激酶 (ALK) 自身磷酸化和下游信号通路。结果：检测到 CUX1-ALK 融合基因后，对原发肿瘤标本的福尔马林固定石蜡包埋切片进行 RNA 测序分析，揭示了插入 ALK 外显子第 53 位核苷酸之前的 CUX1 内含子 8 的 97 个核苷酸片段。 20. cut-like homeobox 1-ALK 融合蛋白在 293T 细胞中的表达证实了融合蛋白的自磷酸化和 ALK 下游信号通路的激活，包括丝裂原活化蛋白激酶、Janus 激酶-信号转导和激活剂转录和磷酸肌醇 3-激酶/AKT 信号通路，这都可以通过添加克唑替尼来抑制。此外，患者对克唑替尼表现出优异的反应，无进展生存期为 20 个月。结论：本研究提供了来自 NSCLC 患者的 CUX1-ALK 融合基因的新发现，可以为 NSCLC 患者提供最大利益的个性化治疗解决方案。