Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
Nature. 2021 Dec;600(7888):319-323. doi: 10.1038/s41586-021-04135-5. Epub 2021 Nov 24.
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). However, such oncogenic drivers are not found in 25-40% of cases of lung adenocarcinoma, the most common histological subtype of NSCLC. 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。针对致癌驱动因素的靶向治疗已显著改善了非小细胞肺癌（NSCLC）患者的治疗效果。然而，在 25-40%的肺腺癌病例中并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。在这里，我们使用全转录组测序在多机构基因组筛选平台（LC-SCRUM-Asia，UMIN000036871）中鉴定出一种新的 CLIP1 和 LTK 融合转录本。CLIP1-LTK 融合在 0.4%的 NSCLC 中存在，且与其他已知的致癌驱动因素互斥。我们表明，CLIP1-LTK 融合蛋白的激酶活性持续激活并具有转化潜能。用 ALK 抑制剂 lorlatinib 处理表达 CLIP1-LTK 的 Ba/F3 细胞，可抑制 CLIP1-LTK 激酶活性，抑制增殖并诱导细胞凋亡。一名 NSCLC 患者携带 CLIP1-LTK 融合，对 lorlatinib 治疗有良好的临床反应。据我们所知，这是首次描述 LTK 改变具有致癌活性的癌症。这些结果确定了 CLIP1-LTK 融合是 NSCLC 的一个潜在治疗靶点，可用 lorlatinib 进行治疗。
