| Popis: |
Lung cancer is one of the most aggressive tumors. Targeted therapies stratified by oncogenic drivers has remarkably improved therapeutic outcomes in patients with non-small cell lung cancer (NSCLC) (1). However, such oncogenic drivers are not found in 25-40% of NSCLC cases (2). Here, we identified 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 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 NSCLC patient harboring the CLIP1-LTK fusion showed dramatic clinical responses to lorlatinib treatment. To our knowledge, this is the first description of LTK alterations with oncogenic activity in cancers. Our results demonstrate that the CLIP1-LTK fusion is a novel target in NSCLC, which could be treated with lorlatinib. |
