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      OncoTargets and Therapy (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the pathological basis of cancers, potential targets for therapy and treatment protocols to improve the management of cancer patients. Publishing high-quality, original research on molecular aspects of cancer, including the molecular diagnosis, since 2008. Sign up for email alerts here. 50,877 Monthly downloads/views I 4.345 Impact Factor I 7.0 CiteScore I 0.81 Source Normalized Impact per Paper (SNIP) I 0.811 Scimago Journal & Country Rank (SJR)

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      Successful long-term treatment of non–small cell lung cancer positive for RET rearrangement with pemetrexed


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          The discovery of RET rearrangement in non–small cell lung cancer (NSCLC) has prompted development of molecularly targeted therapy for such tumors, with several clinical trials being under way to evaluate the therapeutic effects of multitargeted tyrosine kinase inhibitors. The sensitivity of RET fusion–positive NSCLC to cytotoxic chemotherapy has remained unclear, however. We here report a case of NSCLC positive for the CCDC6-RET fusion gene that benefited from treatment with pemetrexed over a period of 30 months, suggesting that thymidylate synthase–targeted drugs such as pemetrexed may show efficacy for NSCLC harboring RET fusions.

          Most cited references8

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          RET, ROS1 and ALK fusions in lung cancer.

          Through an integrated molecular- and histopathology-based screening system, we performed a screening for fusions of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1, receptor tyrosine kinase (ROS1) in 1,529 lung cancers and identified 44 ALK-fusion-positive and 13 ROS1-fusion-positive adenocarcinomas, including for unidentified fusion partners for ROS1. In addition, we discovered previously unidentified kinase fusions that may be promising for molecular-targeted therapy, kinesin family member 5B (KIF5B)-ret proto-oncogene (RET) and coiled-coil domain containing 6 (CCDC6)-RET, in 14 adenocarcinomas. A multivariate analysis of 1,116 adenocarcinomas containing these 71 kinase-fusion-positive adenocarcinomas identified four independent factors that are indicators of poor prognosis: age ≥ 50 years, male sex, high pathological stage and negative kinase-fusion status.
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            KIF5B-RET fusions in lung adenocarcinoma.

            We identified in-frame fusion transcripts of KIF5B (the kinesin family 5B gene) and the RET oncogene, which are present in 1-2% of lung adenocarcinomas (LADCs) from people from Japan and the United States, using whole-transcriptome sequencing. The KIF5B-RET fusion leads to aberrant activation of RET kinase and is considered to be a new driver mutation of LADC because it segregates from mutations or fusions in EGFR, KRAS, HER2 and ALK, and a RET tyrosine kinase inhibitor, vandetanib, suppresses the fusion-induced anchorage-independent growth activity of NIH3T3 cells.
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              Thymidylate synthase as a determinant of pemetrexed sensitivity in non-small cell lung cancer

              Background: Although a high level of thymidylate synthase (TS) expression in malignant tumours has been suggested to be related to a reduced sensitivity to the antifolate drug pemetrexed, no direct evidence for such an association has been demonstrated in non-small cell lung cancer (NSCLC). We have now investigated the effect of TS overexpression on pemetrexed sensitivity in NSCLC cells. Methods: We established NSCLC cell lines that stably overexpress TS and examined the effects of such overexpression on the cytotoxicity of pemetrexed both in vitro and in xenograft models. We further examined the relation between TS expression in tumour specimens from NSCLC patients and the tumour response to pemetrexed by immunohistochemical analysis. Results: The sensitivity of NSCLC cells overexpressing TS to the antiproliferative effect of pemetrexed was markedly reduced compared with that of control cells. The inhibition of DNA synthesis and induction of apoptosis by pemetrexed were also greatly attenuated by forced expression of TS. Furthermore, tumours formed by TS-overexpressing NSCLC cells in nude mice were resistant to the growth-inhibitory effect of pemetrexed observed with control tumours. Finally, the level of TS expression in tumours of non-responding patients was significantly higher than that in those of responders, suggestive of an inverse correlation between TS expression and tumour response to pemetrexed. Conclusion: A high level of TS expression confers a reduced sensitivity to pemetrexed. TS expression is thus a potential predictive marker for response to pemetrexed-based chemotherapy in NSCLC patients.

                Author and article information

                Onco Targets Ther
                Onco Targets Ther
                OncoTargets and therapy
                08 July 2019
                : 12
                : 5355-5358
                [1 ]Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan
                [2 ]Department of Genome Biology, Kindai University Faculty of Medicine , Osaka-Sayama, Osaka 589-8511, Japan
                Author notes
                Correspondence: Masayuki TakedaDepartment of Medical Oncology, Kindai University Faculty of Medicine , 377-2 Ohno-Higashi, Osaka-Sayama, Osaka589-8511, JapanTel +81 72 366 0221Email takeda_m@ 123456med.kindai.ac.jp
                © 2019 Takeda et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                : 09 April 2019
                : 21 June 2019
                Page count
                Figures: 2, References: 14, Pages: 4
                Case Report

                Oncology & Radiotherapy
                ccdc6-ret,non–small cell lung cancer,pemetrexed,predictive marker
                Oncology & Radiotherapy
                ccdc6-ret, non–small cell lung cancer, pemetrexed, predictive marker


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