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

被引：54

作者：

Izumi, Hiroki ^{[1
]}

Matsumoto, Shingo ^{[1
]}

Liu, Jie ^{[2
]}

Tanaka, Kosuke ^{[2
]}

Mori, Shunta ^{[1
]}

Hayashi, Kumiko ^{[3
]}

Kumagai, Shogo ^{[4
]}

Shibata, Yuji ^{[1
]}

Hayashida, Takuma ^{[2
,5
]}

Watanabe, Kana ^{[6
]}

Fukuhara, Tatsuro ^{[6
]}

Ikeda, Takaya ^{[1
]}

Yoh, Kiyotaka ^{[1
]}

Kato, Terufumi ^{[7
]}

Nishino, Kazumi ^{[8
]}

Nakamura, Atsushi ^{[9
]}

Nakachi, Ichiro ^{[10
]}

Kuyama, Shoichi ^{[11
]}

Furuya, Naoki ^{[12
]}

Sakakibara-Konishi, Jun ^{[13
]}

Okamoto, Isamu ^{[14
]}

Taima, Kageaki ^{[15
]}

Ebi, Noriyuki ^{[16
]}

Daga, Haruko ^{[17
]}

Yamasaki, Akira ^{[18
]}

Kodani, Masahiro ^{[18
]}

Udagawa, Hibiki ^{[1
,2
]}

Kirita, Keisuke ^{[1
]}

Zenke, Yoshitaka ^{[1
]}

Nosaki, Kaname ^{[1
]}

Sugiyama, Eri ^{[1
]}

Sakai, Tetsuya ^{[1
]}

Nakai, Tokiko ^{[19
]}

Ishii, Genichiro ^{[19
]}

Niho, Seiji ^{[1
]}

Ohtsu, Atsushi ^{[20
]}

Kobayashi, Susumu S. ^{[2
,5
,21
]}

Goto, Koichi ^{[1
]}

机构：

[1] Natl Canc Ctr Hosp East, Dept Thorac Oncol, Kashiwa, Chiba, Japan

[2] Natl Canc Ctr, Div Translat Genom, Exploratory Oncol Res & Clin Trial Ctr, Kashiwa, Chiba, Japan

[3] LSI Medience Corp Cent Lab, Itabashi Ku, Tokyo, Japan

[4] Natl Canc Ctr, Div Canc Immunol, Res Inst, Exploratory Oncol Res & Clin Trial Ctr, Kashiwa, Chiba, Japan

[5] Univ Tokyo, Grad Sch Frontier Sci, Dept Integrated Biosci, Kashiwa, Chiba, Japan

[6] Miyagi Canc Ctr, Dept Resp Med, Natori, Miyagi, Japan

[7] Kanagawa Canc Ctr, Dept Thorac Oncol, Yokohama, Kanagawa, Japan

[8] Osaka Int Canc Inst, Dept Thorac Oncol, Osaka, Japan

[9] Sendai Kousei Hosp, Dept Pulm Med, Sendai, Miyagi, Japan

[10] Saiseikai Utsunomiya Hosp, Div Pulm, Dept Internal Med, Utsunomiya, Tochigi, Japan

[11] Natl Hosp Org Iwakuni Clin Ctr, Dept Resp Med, Iwakuni, Japan

[12] St Marianna Univ, Dept Internal Med, Div Resp Med, Sch Med, Kawasaki, Kanagawa, Japan

[13] Hokkaido Univ Hosp, Dept Med 1, Sapporo, Hokkaido, Japan

[14] Kyushu Univ, Res Inst Dis Chest, Grad Sch Med Sci, Fukuoka, Japan

[15] Hirosaki Univ, Dept Resp Med, Grad Sch Med, Hirosaki, Aomori, Japan

[16] Iizuka Hosp, Dept Resp Med, Iizuka, Fukuoka, Japan

[17] Osaka City Gen Hosp, Dept Med Oncol, Osaka, Japan

[18] Tottori Univ, Dept Multidisciplinary Internal Med, Div Resp Med & Rheumatol, Fac Med, Yonago, Tottori, Japan

[19] Natl Canc Ctr, Dept Pathol & Clin Labs, Kashiwa, Chiba, Japan

[20] Natl Canc Ctr Hosp East, Dept Gastroenterol & Gastrointestinal Oncol, Kashiwa, Chiba, Japan

[21] Harvard Med Sch, Dept Med, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA

来源：

NATURE | 2021年 / 600卷 / 7888期

关键词：

OVERCOMES RESISTANCE; EXPRESSION; INHIBITOR; CLIP-170; GENE; RET;

D O I：

10.1038/s41586-021-04135-5

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：319 / +

页数：21

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