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Izumi, Hiroki; Matsumoto, Shingo; Liu, Jie; Tanaka, Kosuke; Mori, Shunta; Hayashi, Kumiko; Kumagai, Shogo; Shibata, Yuji; Hayashida, Takuma; Watanabe, Kana; Fukuhara, Tatsuro; Ikeda, Takaya; Yoh, Kiyotaka; Kato, Terufumi; Nishino, Kazumi; Nakamura, Atsushi; Nakachi, Ichiro; Kuyama, Shoichi; Furuya, Naoki; Sakakibara-Konishi, Jun; Okamoto, Isamu; Taima, Kageaki; Ebi, Noriyuki; Daga, Haruko; Yamasaki, Akira; Kodani, Masahiro; Udagawa, Hibiki; Kirita, Keisuke; Zenke, Yoshitaka; Nosaki, Kaname; Sugiyama, Eri; Sakai, Tetsuya; Nakai, Tokiko; Ishii, Genichiro; Niho, Seiji; Ohtsu, Atsushi; Kobayashi, Susumu S; Goto, Koichi
Nature (London), 12/2021, Volume: 600, Issue: 7888Journal Article
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.
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