Lung cancer is one of the most aggressive tumour types. Targeted therapies stratified by oncogenic drivers have substantially improved therapeutic outcomes in patients with non-small-cell lung cancer (NSCLC)¹. However, such oncogenic drivers are not found in 25–40% of cases of lung adenocarcinoma, the most common histological subtype of NSCLC². Here we identify a novel fusion transcript of CLIP1 and LTK using whole-transcriptome sequencing in a multi-institutional genome screening platform (LC-SCRUM-Asia, UMIN000036871). The CLIP1–LTK fusion was present in 0.4% of NSCLCs and was mutually exclusive with other known oncogenic drivers. We show that kinase activity of the CLIP1–LTK fusion protein is constitutively activated and has transformation potential. Treatment of Ba/F3 cells expressing CLIP1–LTK with lorlatinib, an ALK inhibitor, inhibited CLIP1–LTK kinase activity, suppressed proliferation and induced apoptosis. One patient with NSCLC harbouring the CLIP1–LTK fusion showed a good clinical response to lorlatinib treatment. To our knowledge, this is the first description of LTK alterations with oncogenic activity in cancers. These results identify the CLIP1–LTK fusion as a target in NSCLC that could be treated with lorlatinib.

肺癌是最具侵袭性的肿瘤类型之一。按致癌驱动因素分层的靶向治疗显着改善了非小细胞肺癌 (NSCLC) 患者的治疗效果¹。然而，在 25-40% 的肺腺癌病例中未发现此类致癌驱动因素，肺腺癌是 NSCLC 最常见的组织学亚型²。在这里，我们在多机构基因组筛选平台 (LC-SCRUM-Asia, UMIN000036871) 中使用全转录组测序鉴定了CLIP1和LTK的新融合转录本。CLIP1 –LTK融合存在于 0.4% 的非小细胞肺癌中，并且与其他已知的致癌驱动因素相互排斥。我们表明 CLIP1–LTK 融合蛋白的激酶活性是组成性激活的，并且具有转化潜力。用 ALK 抑制剂劳拉替尼处理表达 CLIP1-LTK 的 Ba/F3 细胞，抑制 CLIP1-LTK 激酶活性，抑制增殖并诱导细胞凋亡。一名携带CLIP1-LTK融合基因的 NSCLC 患者对劳拉替尼治疗表现出良好的临床反应。据我们所知，这是对LTK改变与癌症致癌活性的首次描述。这些结果将 CLIP1-LTK融合确定为 NSCLC 中可以用劳拉替尼治疗的靶点。