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-KonishiIsamu 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, Koichi Goto

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)319-323
Number of pages5
JournalNature
Volume600
Issue number7888
DOIs
Publication statusPublished - Dec 9 2021
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General

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