The CLIP1-LTK fusion is an oncogenic driver in non-small-cell lung cancer.
The CLIP1-LTK fusion is an oncogenic driver in non-small-cell lung cancer.
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DOI：
10.1038/s41586-021-04135-5
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发表时间：
2021-12
期刊：
影响因子：
64.8
通讯作者：
Goto K
中科院分区：
文献类型：
--
作者：
Izumi H;Matsumoto S;Liu J;Tanaka K;Mori S;Hayashi K;Kumagai S;Shibata Y;Hayashida T;Watanabe K;Fukuhara T;Ikeda T;Yoh K;Kato T;Nishino K;Nakamura A;Nakachi I;Kuyama S;Furuya N;Sakakibara-Konishi J;Okamoto I;Taima K;Ebi N;Daga H;Yamasaki A;Kodani M;Udagawa H;Kirita K;Zenke Y;Nosaki K;Sugiyama E;Sakai T;Nakai T;Ishii G;Niho S;Ohtsu A;Kobayashi SS;Goto K
肺癌是最具侵袭性的肿瘤之一。按致癌驱动因素分层的靶向治疗显著改善了非小细胞肺癌（NSCLC）患者的治疗结局。然而，在25-40%的NSCLC病例中未发现此类致癌驱动因素。在这里，我们在多机构基因组筛选平台（LC-SCRUM-Asia，UMIN 000036871）中使用全转录组测序鉴定了CLIP 1和LTK的新型融合转录物。CLIP 1-LTK融合存在于0.4%的NSCLC中，并且与其他已知的致癌驱动因子相互排斥。我们发现CLIP 1-LTK融合蛋白的激酶活性是组成性激活的，并且具有转化潜力。用ALK抑制剂劳拉替尼处理表达CLIP 1-LTK的Ba/F3细胞，可抑制CLIP 1-LTK激酶活性，抑制增殖并诱导凋亡。1例携带CLIP 1-LTK融合的NSCLC患者对劳拉替尼治疗显示出显著的临床应答。据我们所知，这是第一次描述癌症中具有致癌活性的LTK改变。我们的研究结果表明，CLIP 1-LTK融合是NSCLC的一个新靶点，可以用劳拉替尼治疗。
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) . However, such oncogenic drivers are not found in 25-40% of NSCLC cases . 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.
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影响因子：
5.7
作者：
Saito M;Shiraishi K;Kunitoh H;Takenoshita S;Yokota J;Kohno T
通讯作者：
Kohno T
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
51.1
作者：
Drilon, Alexander;Rekhtman, Natasha;Arcila, Maria;Wang, Lu;Ni, Andy;Albano, Melanie;Van Voorthuysen, Martine;Somwar, Romel;Smith, Roger S.;Montecalvo, Joseph;Plodkowski, Andrew;Ginsberg, Michelle S.;Riely, Gregory J.;Rudin, Charles M.;Ladanyi, Marc;Kris, Mark G.
通讯作者：
Kris, Mark G.
影响因子：
15.8
作者：
Greulich H;Chen TH;Feng W;Jänne PA;Alvarez JV;Zappaterra M;Bulmer SE;Frank DA;Hahn WC;Sellers WR;Meyerson M
通讯作者：
Meyerson M
影响因子：
1.2
作者：
Borowicz, Stanley;Van Scoyk, Michelle;Winn, Robert A.
通讯作者：
Winn, Robert A.