TY - JOUR
T1 - The CLIP1–LTK fusion is an oncogenic driver in non‐small‐cell lung cancer
AU - Izumi, Hiroki
AU - Matsumoto, Shingo
AU - Liu, Jie
AU - Tanaka, Kosuke
AU - Mori, Shunta
AU - Hayashi, Kumiko
AU - Kumagai, Shogo
AU - Shibata, Yuji
AU - Hayashida, Takuma
AU - Watanabe, Kana
AU - Fukuhara, Tatsuro
AU - Ikeda, Takaya
AU - Yoh, Kiyotaka
AU - Kato, Terufumi
AU - Nishino, Kazumi
AU - Nakamura, Atsushi
AU - Nakachi, Ichiro
AU - Kuyama, Shoichi
AU - Furuya, Naoki
AU - Sakakibara-Konishi, Jun
AU - Okamoto, Isamu
AU - Taima, Kageaki
AU - Ebi, Noriyuki
AU - Daga, Haruko
AU - Yamasaki, Akira
AU - Kodani, Masahiro
AU - Udagawa, Hibiki
AU - Kirita, Keisuke
AU - Zenke, Yoshitaka
AU - Nosaki, Kaname
AU - Sugiyama, Eri
AU - Sakai, Tetsuya
AU - Nakai, Tokiko
AU - Ishii, Genichiro
AU - Niho, Seiji
AU - Ohtsu, Atsushi
AU - Kobayashi, Susumu S.
AU - Goto, Koichi
N1 - Funding Information:
Acknowledgements We thank Y. Murata and PREMIA for administrative assistance with managing clinical samples, molecular screening and the clinico-genomic database in LC-SCRUM-Asia; and T. Y. Morita for assistance with flow cytometry analyses. This work was supported by the Princess Takamatsu Cancer Research Fund 18-250 (S.S.K.), JSPS KAKENHI Grant Number JP20K17215 (H.I.), JP16K21746 (S.S.K.) and JP21K15541 (K. Tanaka.), the National Cancer Center Research and Development Fund 31-A-5 (A.O.), 31-A-6 (S.S.K) and 28-A-6 (K.G.), and AMED Grant Number JP21ck0106289 (K.G.), JP21ck0106294 (K.Y.), JP21ck0106483 (K. Nosaki), JP21ck0106568 (K.G.), JP20ck0106411 (S. Matsumoto), JP20ck0106449 (I.O.), JP20ck0106450 (S.N.), JP20ak0101050 (K. Tsuchihara), JP18Ik0201056 (A.O.), JP18kk0205004 (H. Nakagama), JP17Ack0106148 (K.G.), JP17Ack0106147 (S. Yano), and JP16ck0106041 (K.G.). Molecular screening in LC-SCRUM-Asia was supported by Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Daiichi sankyo, Eisai, Janssen, Kyowa kirin, Merck, Medical & Biological Laboratories, MSD, Novartis, Ono, Pfizer, Sumitomo Dainippon, Taiho and Takeda. WTS was supported by Merus.
Funding Information:
Competing interests H.I. reports research support from Amgen and personal fees (honoraria) from Ono. S. Matsumoto reports research support from Chugai, Novartis, Eli Lilly, Merck and MSD, and personal fees (honoraria) from AstraZeneca, Chugai, Novartis, Pfizer and Eli Lilly. Y.S. reports research support from MSD, and personal fees (honoraria) from Ono, Pfizer, Chugai, Novartis, Bristol-Myers Squibb, AstraZeneca and Taiho Pharmaceutical Co. T.F. reports research support from Pfizer, Chgai, Novartis and AstraZeneca. K.Y. reports research support from AstraZeneca, Eli Lilly, Pfizer, Daiichi sankyo, Abbvie, Taiho, Bayer, Takeda and MSD, and personal fees (honoraria) from AstraZeneca, Bristol-Myers Squibb, Chugai, Daiichi sankyo, Janssen, Eli Lilly, Taiho, Novartis, Kyowa kirin and Boehringer Ingelheim. T.K. reports research support from Pfizer, Chugai, Takeda, Novartis, Turning Point Therapeutics and AstraZeneca, and personal fees (honoraria) from Pfizer, Chugai, Takeda, Novartis and AstraZeneca. K. Nishino reports research support from Pfizer and personal fees (honoraria) from Pfizer, Chugai, Takeda, Novartis and AstraZeneca. A.N. reports personal fees (honoraria) from Chgai and Novartis. S. Kuyama reports personal fees (honoraria) from Pfizer, Chugai and AstraZeneca. N.F. reports personal fees (honoraria) from Pfizer, Chugai, Novartis and AstraZeneca. I.O. reports research support from Chugai, Takeda and Novartis, and personal fees (honoraria) from Pfizer, Chugai, Novartis and AstraZeneca. K. Taima. reports personal fees (honoraria) from Chugai, Novartis and AstraZeneca. H.D. reports research support from Pfizer, Chugai and Takeda, and personal fees from Chugai. A.Y. reports personal fees (honoraria) from Takeda. K.K. reports personal fees (honoraria) from Pfizer, Chugai, Novartis and AstraZeneca. Y.Z. reports research support from AstraZeneca and personal fees (honoraria) from Pfizer, Chugai, Takeda and AstraZeneca. K. Nosaki reports research support from Chugai and Takeda, and personal fees (honoraria) from Pfizer, Chugai, Takeda, Novartis and AstraZeneca. T.S. reports personal fees (honoraria) from Chugai and AstraZeneca. G.I. reports research support from Takeda and personal fees (honoraria) from Pfizer, Chugai, Takeda, Novartis and AstraZeneca. S.N. reports research support from Pfizer, Chugai, Takeda and AstraZeneca, and personal fees (honoraria) from Pfizer, Chugai, Takeda, Novartis and AstraZeneca. A.O. reports personal fees (honoraria) from Chugai. S.S.K. reports research support from Boehringer Ingelheim, MiNA Therapeutics and Taiho Therapeutics, as well as personal fees (honoraria) from Boehringer Ingelheim, Bristol Meyers Squibb, AstraZeneca, Chugai Pharmaceutical and Takeda Pharmaceuticals, all outside of the submitted work. K.G. reports research support from Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Daiichi sankyo, Eisai, Eli Lilly, Guardant Health, Janssen, Kyowa Kirin, Life Technologies Japan, MSD, Novartis, Ono, Otsuka, Pfizer, Taiho and Takeda, and personal fees (honoraria) from Bristol-Myers Squibb, Chugai, Daiichi sankyo, Eisai, Eli Lilly, Haihe Biopharma, Ignyta, Janssen, KISSEI, Kyowa Kirin, LOXO Oncology, Medical & Biological Laboratories, Merck Biopharma, Merus, MSD, Ono, Pfizer, Sumitomo Dainippon Pharma, Shanghai Haihe, Sysmex Corporation, Taiho, Takeda, and Xcoo. The authors report no other competing interests.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/12/9
Y1 - 2021/12/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85120644586&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85120644586&partnerID=8YFLogxK
U2 - 10.1038/s41586-021-04135-5
DO - 10.1038/s41586-021-04135-5
M3 - Article
C2 - 34819663
AN - SCOPUS:85120644586
VL - 600
SP - 319
EP - 323
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7888
ER -
