The CLIP1–LTK fusion is an oncogenic driver in non‐small‐cell lung cancer

Hiroki Izumi, Shingo Matsumoto, Jie Liu, Kosuke Tanaka, Shunta Mori, Kumiko Hayashi, Shogo Kumagai, Yuji Shibata, Takuma Hayashida, Kana Watanabe, Tatsuro Fukuhara, Takaya Ikeda, Kiyotaka Yoh, Terufumi Kato, Kazumi Nishino, Atsushi Nakamura, Ichiro Nakachi, Shoichi Kuyama, Naoki Furuya, Jun Sakakibara-Konishi, Isamu Okamoto, Kageaki Taima, Noriyuki Ebi, Haruko Daga, Akira Yamasaki, Masahiro Kodani, Hibiki Udagawa, Keisuke Kirita, Yoshitaka Zenke, Kaname Nosaki, Eri Sugiyama, Tetsuya Sakai, Tokiko Nakai, Genichiro Ishii, Seiji Niho, Atsushi Ohtsu, Susumu S. Kobayashi () and Koichi Goto ()
Additional contact information
Hiroki Izumi: National Cancer Center Hospital East
Shingo Matsumoto: National Cancer Center Hospital East
Jie Liu: National Cancer Center
Kosuke Tanaka: National Cancer Center
Shunta Mori: National Cancer Center Hospital East
Kumiko Hayashi: LSI Medience Corporation Central Laboratory
Shogo Kumagai: National Cancer Center
Yuji Shibata: National Cancer Center Hospital East
Takuma Hayashida: National Cancer Center
Kana Watanabe: Miyagi Cancer Center
Tatsuro Fukuhara: Miyagi Cancer Center
Takaya Ikeda: National Cancer Center Hospital East
Kiyotaka Yoh: National Cancer Center Hospital East
Terufumi Kato: Kanagawa Cancer Center
Kazumi Nishino: Osaka International Cancer Institute
Atsushi Nakamura: Sendai Kousei Hospital
Ichiro Nakachi: Saiseikai Utsunomiya Hospital
Shoichi Kuyama: National Hospital Organization Iwakuni Clinical Center
Naoki Furuya: St Marianna University School of Medicine
Jun Sakakibara-Konishi: Hokkaido University Hospital
Isamu Okamoto: Kyushu University
Kageaki Taima: Hirosaki University Graduate School of Medicine
Noriyuki Ebi: Iizuka Hospital
Haruko Daga: Osaka City General Hospital
Akira Yamasaki: Tottori University
Masahiro Kodani: Tottori University
Hibiki Udagawa: National Cancer Center Hospital East
Keisuke Kirita: National Cancer Center Hospital East
Yoshitaka Zenke: National Cancer Center Hospital East
Kaname Nosaki: National Cancer Center Hospital East
Eri Sugiyama: National Cancer Center Hospital East
Tetsuya Sakai: National Cancer Center Hospital East
Tokiko Nakai: National Cancer Center
Genichiro Ishii: National Cancer Center
Seiji Niho: National Cancer Center Hospital East
Atsushi Ohtsu: National Cancer Center Hospital East
Susumu S. Kobayashi: National Cancer Center
Koichi Goto: National Cancer Center Hospital East

Nature, 2021, vol. 600, issue 7888, 319-323

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41586-021-04135-5

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