CLIP1-LTK fusion: A novel druggable gene fusion in NSCLC,
identified using LC-SCRUM-Asia genomic screening platform-A step further to precision medicine-

November 25, 2021
National Cancer Center Japan
Japan Agency for Medical Research and Development

in Japanese

Lung cancer is one of the most aggressive cancers causing an estimated 1.8 million deaths annually worldwide. Over the last two decades, targeted therapies stratified by oncogenic drivers has remarkably improved therapeutic outcomes in　patients with non-small cell lung cancer (NSCLC). However, such oncogenic drivers are not found in 50-60% of NSCLC cases. Therefore, the identification of novel oncogenic kinase alterations should have immediate clinical applications for patients.

In a new publication appearing in Nature, a team of researchers and physicians at National Cancer Center Hospital East and Exploratory Oncology Research & Clinical Trial Center, led by Drs. Koichi Goto and Susumu S. Kobayashi, discovered a novel fusion gene “CLIP1-LTK” by whole-RNA sequencing using a multi-institutional lung cancer genome screening platform. This platform named LC-SCRUM-Asia was originally established in 2013 to identify patients with lung cancer harboring rare targetable oncogene drivers, and to develop effective molecular-targeted therapies. As of November 2021, more than 14,000 lung cancer patients were enrolled into LC-SCRUM-Asia, which has contributed to the clinical development of various targeted therapies, and corresponding companion diagnostics (CDx) for ROS1, BRAF, NTRKs and RET-altered NSCLCs. The CLIP1-LTK fusion was present in 0.4% of NSCLC patients in a mutually exclusive manner with other known oncogenic drivers. The team demonstrates that kinase activity of CLIP1-LTK fusion protein is constitutively activated and has transformation potential. In addition, they found that lorlatinib, an ALK inhibitor, inhibited CLIP1-LTK kinase activity, suppressed proliferation, and induced apoptosis in both cell line and murine models. Based on these preclinical findings, one NSCLC patient harboring the CLIP1-LTK fusion was treated with lorlatinib, and showed dramatic clinical response.

“This study not only shows that CLIP1-LTK is an oncogenic driver in NSCLC, but patients with CLIP1-LTK fusion can be treated by lorlatinib” said the co-leading author Dr. Hiroki Izumi, MD, PhD, National Cancer Center Hospital East. The other co-leading author Dr. Shingo Matsumoto, MD, PhD at the same institution added, “I believe that this oncogenic driver-targeted therapy will be lined up in the molecularly-stratified precision medicine for NSCLC. To do so, urgent clinical development of CDx of LTK fusion and optimized molecular targeted agents are warranted”.

Co-authors included 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.

This work was supported by Japan Agency for Medical Research and Development
(AMED ; JP21ck0106289 , JP21ck0106294 , JP21ck0106483 , JP21ck0106568 , JP20ck0106411 , JP20ck0106449 , JP20ck0106450 , JP20ak0101050 , JP18Ik0201056 , JP18kk0205004 , JP17Ack0106148 , JP17Ack0106147, JP16ck0106041)

Publication

Journal name

Nature

Title

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

Authors

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*, Koichi Goto*

¶ Co-First, * Co-Correspondence

DOI

10.1038/s41586-021-04135-5

URL

https://www.nature.com/articles/s41586-021-04135-5(linked at external site)

Publication date

25 November,2021

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