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

ABSTRACT: 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.

SUBMITTER: Izumi H

PROVIDER: S-EPMC8687755 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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

Izumi Hiroki H Matsumoto Shingo S Liu Jie J Tanaka Kosuke K Mori Shunta S Hayashi Kumiko K Kumagai Shogo S Shibata Yuji Y Hayashida Takuma T Watanabe Kana K Fukuhara Tatsuro T Ikeda Takaya T Yoh Kiyotaka K Kato Terufumi T Nishino Kazumi K Nakamura Atsushi A Nakachi Ichiro I Kuyama Shoichi S Furuya Naoki N Sakakibara-Konishi Jun J Okamoto Isamu I Taima Kageaki K Ebi Noriyuki N Daga Haruko H Yamasaki Akira A Kodani Masahiro M Udagawa Hibiki H Kirita Keisuke K Zenke Yoshitaka Y Nosaki Kaname K Sugiyama Eri E Sakai Tetsuya T Nakai Tokiko T Ishii Genichiro G Niho Seiji S Ohtsu Atsushi A Kobayashi Susumu S SS Goto Koichi K

Nature 20211124 7888

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)<sup>1</sup>. However, such oncogenic drivers are not found in 25-40% of cases of lung adenocarcinoma, the most common histological subtype of NSCLC<sup>2</sup>. Here we identify a novel fusion transcript of CLIP1 and LTK using whole-transcriptome sequencing in a multi-institutional genome sc ...[more]

PMID: 34819663

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Project description:Background and objectiveFor patients with metastatic non-small cell lung cancer (NSCLC) without an oncogenic driver, systemic therapy with immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy have significantly improved the outcomes. However, the majority of patients do not have a durable response, and there is a need for additional predictive biomarkers. The objective of this narrative review is to describe potential biomarkers for immunotherapy.MethodsNarrative overview of the literature synthesizing the findings of literature reporting retrospective, prospective, and subset analyses of studies investigating potential predictive biomarkers for ICI.Key content and findingsTumor expression of programmed death ligand-1 (PD-L1) is the only clinically available biomarker for patients receiving ICI-based therapy. However, PD-L1 has significant limitations and studies have investigated the predictive value of higher PD-L1 expression levels. There has been interest in tumor mutation burden (TMB) based on the premise that a higher TMB would be associated with a more neoantigens, which would increase the likelihood of an immune response. The studies to date have not revealed a consistent association with TMB level and survival benefit. Kelch-like ECH Associated Protein 1 (KEAP1) and serine/threonine kinase 11 (STK11) mutations have been associated with worse outcomes with ICI but these mutations appear to be associated with a worse prognosis, and not predictive for ICI. Tumor infiltrating lymphocytes (TIL's) are the mechanism of immune response, and there is interest in further investigating the presence, type and distribution of TIL's to predict immune benefit. Circulating tumor deoxyribonucleic acid (ctDNA) levels, at baseline and on treatment samples, are being investigated to assess response to therapy and long-term benefit of ICI.ConclusionsNone of the current biomarkers in development are validated for use in routine clinical care. Given the complexity of NSCLC biology and immune response to ICI most likely a composite biomarker using multiple biomarkers will need to be develop.

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

Publications

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

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