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The CLIP1-LTK fusion is an oncogenic driver in non-small-cell lung cancer.


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.

SUBMITTER: Izumi H 

PROVIDER: S-EPMC8687755 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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The CLIP1-LTK fusion is an oncogenic driver in non-small-cell lung cancer.

Izumi Hiroki H   Matsumoto Shingo S   Liu Jie J   Tanaka Kosuke K   Mori Shunta S   Hayashi Kumiko K   Kumagai Shogo S   Shibata Yuji Y   Hayashida Takuma T   Watanabe Kana K   Fukuhara Tatsuro T   Ikeda Takaya T   Yoh Kiyotaka K   Kato Terufumi T   Nishino Kazumi K   Nakamura Atsushi A   Nakachi Ichiro I   Kuyama Shoichi S   Furuya Naoki N   Sakakibara-Konishi Jun J   Okamoto Isamu I   Taima Kageaki K   Ebi Noriyuki N   Daga Haruko H   Yamasaki Akira A   Kodani Masahiro M   Udagawa Hibiki H   Kirita Keisuke K   Zenke Yoshitaka Y   Nosaki Kaname K   Sugiyama Eri E   Sakai Tetsuya T   Nakai Tokiko T   Ishii Genichiro G   Niho Seiji S   Ohtsu Atsushi A   Kobayashi Susumu S SS   Goto Koichi K  

Nature 20211124 7888


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)<sup>1</sup>. However, such oncogenic drivers are not found in 25-40% of cases of lung adenocarcinoma, the most common histological subtype of NSCLC<sup>2</sup>. Here we identify a novel fusion transcript of CLIP1 and LTK using whole-transcriptome sequencing in a multi-institutional genome sc  ...[more]

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