analysis of novel transcript variant of tyrosine kinase gene in small cell lung cancer using the NanoString nCounter

• Project/Area Number: 17K09669
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Juntendo University
• Principal Investigator: Takahashi Fumiyuki 順天堂大学, 医学部, 准教授 (70327823)
• Co-Investigator(Kenkyū-buntansha): 田島 健 順天堂大学, 医学部, 講師 (50384102) ; 茂櫛 薫 順天堂大学, 医学(系)研究科(研究院), 非常勤講師 (60569292) ; 高橋 和久 順天堂大学, 医学部, 教授 (80245711)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 小細胞肺癌 / 分子標的治療薬 / 遺伝子異常 / チロシンキナーゼ / スクリーニング解析 / 遺伝子解析 / 新規治療標的 / 分子標的 / スクリーニング

Outline of Final Research Achievements

Small-cell lung cancer (SCLC) accounts for 15% of all lung cancer cases and is a highly lethal disease. Molecular targeting therapy for SCLC has not been established, and novel therapeutic strategies are urgently needed. In this study, we conducted comprehensive analyses by the NanoString nCounter for 93 tyrosine kinase genes using RNAs from various SCLC cell lines. We identified novel transcript variant of TK gene A by the NanoString nCounter analysis and RNA sequencing. Furthermore, SCLC cell line X harboring novel transcript of TK gene A was highly sensitive to the specific TK inhibitor. These findings suggest that this novel transcript variant of TK gene A may be target for SCLC treatment.

Academic Significance and Societal Importance of the Research Achievements

小細胞肺癌（SCLC）は腫瘍細胞の増殖スピードが速く、早期に全身へ転移しやすいことが知られている。そして初回の抗癌剤治療にはよく反応するものの、容易に多剤耐性を獲得し、再発する極めて予後不良な疾患である。近年、SCLCの進展型症例において抗癌剤と免疫チェックポイント阻害剤の併用療法が臨床導入されているが、未だに有効な分子標的治療薬の臨床応用には至っておらず、その開発は急務である。本研究で同定された遺伝子転写変異体については過去に報告がなく、その遺伝子異常をSCLCの実診療においてスクリーニングすることは、現在、極めて難治性疾患であるSCLC患者の予後改善に貢献できる可能性があると考えられる。

Research Products

• [Journal Article] Activation of insulin-like growth factor-1 receptor confers acquired resistance to osimertinib in non-small cell lung cancer with EGFR T790M mutation (2020)
  • Author(s): Hayakawa D, Takahashi F, Mitsuishi Y, Tajima K, Hidayat M, Winardi W, Ihara H, Kanamori K, Matsumoto N, Asao T, Ko R, Shukuya T, Takamochi K, Hayashi T, Suehara Y, Takeda Nakamura I, Ueno T, Kohsaka S, Mano H, Takahashi K
  • Journal Title: Thorac Cancer Volume: 11 Issue: 1 Pages: 140-149
  • DOI: 10.1111/1759-7714.13255
  • Peer Reviewed / Open Access
• [Journal Article] Identification of Novel CD74-NRG2α Fusion From Comprehensive Profiling of Lung Adenocarcinoma in Japanese Never or Light Smokers (2020)
  • Author(s): Kohsaka S, Hayashi T, Nagano M, Ueno T, Kojima S, Kawazu M, Shiraishi Y, Kishikawa S, Suehara Y, Takahashi F, Takahashi K, Suzuki K, Takamochi K, Mano H
  • Journal Title: Journal of Thoracic Oncology Volume: － Issue: 6 Pages: 30098-8
  • DOI: 10.1016/j.jtho.2020.01.021
  • Peer Reviewed / Open Access
• [Journal Article] Clinicopathological characteristics of lung adenocarcinoma with compound EGFR mutations. (2020)
  • Author(s): Hayashi T, Kohsaka S, Takamochi K, Hara K, Kishikawa S, Sano K, Takahashi F, Suehara Y, Saito T, Takahashi K, Suzuki K, Yao T.
  • Journal Title: Human Pathology Volume: 14 Pages: 42-51
  • DOI: 10.1016/j.humpath.2020.07.007
  • Peer Reviewed
• [Journal Article] Comprehensive assay for the molecular profiling of cancer by target enrichment from formalin‐fixed paraffin‐embedded specimens (2019)
  • Author(s): Kohsaka Shinji、Tatsuno Kenji、Ueno Toshihide、et al.
  • Journal Title: Cancer Science Volume: 110 Issue: 4 Pages: 1464-1479
  • DOI: 10.1111/cas.13968
  • Peer Reviewed / Open Access
• [Journal Article] Proteomic signatures corresponding to the SS18/SSX fusion gene in synovial sarcoma. (2018)
  • Author(s): Ishii M, Suehara Y, Sano K, Kohsaka S, Hayashi T, Kazuno S, Akaike K, Mukaihara K, Kim Y, Okubo T, Takamochi K, Takahashi F, Kaneko K, Saito T.
  • Journal Title: Oncotarget Volume: 9(101) Issue: 101 Pages: 37509-37519
  • DOI: 10.18632/oncotarget.26493
  • Peer Reviewed / Open Access
• [Journal Article] EGFR promotes glioma progression by regulating xCT and GluN2B-containing NMDA receptor signaling. (2018)
  • Author(s): Suina K, Tsuchihashi K, Yamasaki J, Kamenori S, Shintani S, Hirata Y, Okazaki S, Sampetrean O, Baba E, Akashi K, Takahashi F, Takahashi K, Saya H, Nagano O.
  • Journal Title: Cancer Science Volume: 109 Issue: 12 Pages: 3874-3882
  • DOI: 10.1111/cas.13826
  • Peer Reviewed / Open Access
• [Journal Article] Next-generation sequencing analysis for gastric adenocarcinoma with enteroblastic differentiation: emphasis on the relationship with hepatoid adenocarcinoma. (2018)
  • Author(s): 1.Akazawa Y, Saito T, Hayashi T, Yanai Y, Tsuyama S, Akaike K, Suehara Y, Takahashi F, Takamochi K, Ueyama H, Murakami T, Watanabe S, Nagahara A, Yao T.
  • Journal Title: Hum Pathol Volume: 78 Pages: 79-88
  • DOI: 10.1016/j.humpath.2018.04.022
  • Peer Reviewed / Open Access
• [Journal Article] Non-small cell lung carcinoma with diffuse co-expression of thyroid transcription factor-1 and ΔNp63/p40 (2018)
  • Author(s): Hayashi Takuo、Takamochi Kazuya、Yanai Yuka、Mitani Keiko、Tomita Hisashi、Mogushi Kaoru、Suehara Yoshiyuki、Takahashi Fumiyuki、Suzuki Kenji、Saito Tsuyoshi、Yao Takashi
  • Journal Title: Human Pathology Volume: S0046-8177 Pages: 30037-6
  • DOI: 10.1016/j.humpath.2018.01.023
  • Peer Reviewed / Open Access
• [Journal Article] A method of high-throughput functional evaluation of EGFR gene variants of unknown significance in cancer (2017)
  • Author(s): Kohsaka Shinji、Nagano Masaaki、Ueno Toshihide、Suehara Yoshiyuki、Hayashi Takuo、Shimada Naoko、Takahashi Kazuhisa、Suzuki Kenji、Takamochi Kazuya、Takahashi Fumiyuki、Mano Hiroyuki
  • Journal Title: Science Translational Medicine Volume: 9 Issue: 416 Pages: 6566-6566
  • DOI: 10.1126/scitranslmed.aan6566
  • Peer Reviewed / Open Access
• [Journal Article] LSD1/KDM1 isoform LSD1+8a contributes to neural differentiation in small cell lung cancer (2017)
  • Author(s): Jotatsu, T., Yagishita, S., Tajima, K., Takahashi, F., Mogushi, K., Hidayat, M., Wirawan, A., Ko, R., Kanemaru, R., Shimada, N., Mitani, K., Saito, T., Takamochi, K., Suzuki, K., Kohsaka, S., Kojima, S., Mukae, H., Yatera, K., and Takahashi, K.
  • Journal Title: Biochemistry and Biophysics Reports Volume: ９ Pages: 86-94
  • DOI: 10.1016/j.bbrep.2016.11.015
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] DNA mismatch repair deficiency in surgically resected lung adenocarcinoma: Microsatellite instability analysis using the Promega panel (2017)
  • Author(s): Takamochi Kazuya、Takahashi Fumiyuki、Suehara Yoshiyuki、Sato Eiichi、Kohsaka Shinji、Hayashi Takuo、Kitano Shigehisa、Uneno Toshihide、Kojima Shinya、Takeuchi Kengo、Mano Hiroyuki、Suzuki Kenji
  • Journal Title: Lung cancer Volume: 110 Pages: 26-31
  • DOI: 10.1016/j.lungcan.2017.05.016
  • Peer Reviewed / Open Access
• [Presentation] インスリン様成長因子1受容体の活性化はT790M遺伝子変異陽性NSCLCにおけるオシメルチニブ耐性に寄与する (2020)
  • Author(s): 早川乃介、髙橋史行、光石陽一郎、田島健、中村育子、松本直久、金森幸一郎、高遼、朝尾哲彦、宿谷威仁、嶋村尚子、和泉研太、Wira Winardi、白井由紀奈、虎澤匡洋、三浦啓太、藤岡雅大、高橋和久
  • Organizer: 第61回日本肺癌学会学術集会
• [Presentation] 進行EGFR遺伝子変異/ALK融合遺伝子陽性NSCLCにおける、治療開始後5年以降の経過の検討 (2020)
  • Author(s): 嶋村尚子，宿谷威仁，藤岡雅大，朝尾哲彦，白井由紀奈，三浦啓太, 和泉研太, 早川乃介，高遼，光石陽一郎，田島健，柴山里奈，嶋田奈緒子，髙橋史行，高橋和久
  • Organizer: 第61回日本肺癌学会学術集会
• [Presentation] 重複癌の既往と進行非小細胞肺癌に対する1次治療ペムブロリズマブの治療効果との関連の検討 (2020)
  • Author(s): 三浦啓太、宿谷威仁、朝尾哲彦、阿部瞳、白井由紀奈、和泉研太、早川乃介、松本直久、金森幸一郎、嶋村尚子、光石陽一郎、田島健、柴山里奈、嶋田奈緒子、高橋史行、高遼、高橋和久
  • Organizer: 第61回日本肺癌学会学術集会
• [Presentation] SLC7A11 expression confers cancer stem-like properties in small cell lung cancer cells (2019)
  • Author(s): Kamenori S, Suina K, Yamasaki J, Shintani S, Otsuki Y, Hirata Y, Okazaki S, Tsuchihashi K, Sampetrean O, Mitsuishi Y, Takahashi F, Takahashi K, Saya H, Nagano O
  • Organizer: American Association of Cancer Research(AACR) Annual Meeting
  • Int'l Joint Research
• [Presentation] Nrf2 expression in surgically resected lung adenocarcinomas: Its association with clinicopathologic features and driver oncogene alterations (2019)
  • Author(s): Takamochi K, Hayashi T, Hara K, Mitsuishi Y, Takahashi F, Suehara Y, Suzuki K
  • Organizer: European Society for Medical Oncology (ESMO), International Conference
  • Int'l Joint Research
• [Presentation] Clinicopathological characteristics of lung adenocarcinoma with EGFR compound mutations. (2019)
  • Author(s): Hayashi T, Kohsaka S, Takamochi K, Takahashi F, Suehara Y, Saito T, Suzuki K, Mano H, Yao T
  • Organizer: United States and Canadian Academy of Pathology (USCAP)
  • Int'l Joint Research
• [Presentation] The role of histone deacetylase in the maintenance of gefitinib-resistant lung cancer stem cells with epidermal growth factor receptor mutation. (2018)
  • Author(s): Nurwidya F, Takahashi F, Hidayat M, Wirawan A, Baskoro H, Kato M, Tajima K, Shimada N, Andarini S.L, Yunus F, Takahashi K.
  • Organizer: American Thoracic Society 2018 International Conference
  • Int'l Joint Research
• [Presentation] Pneumothorax in patients with idiopathic interstitial pneumonias. (2018)
  • Author(s): Haraguchi M, Kato M, Nakamura T, Horikoshi K, Yoshikawa H, Ihara H, Asao T, Okamoto S, Takagi H, Takahashi F, Sekiya M, Seyama K, Takahashi K.
  • Organizer: American Thoracic Society 2018 International Conference
  • Int'l Joint Research
• [Presentation] Usual interstitial pneumonia pattern in the lower lung lobes as a prognostic factor in idiopathic pleuroparenchymal fibroelastosis. (2018)
  • Author(s): Kono K, Kato M, Nakamura T, Yamada T, Tajima M, Ihara H, Tajima K, Shiota S, Takahashi F, Sasaki S, Seyama K, Takahashi K.
  • Organizer: American Thoracic Society 2018 International Conference
  • Int'l Joint Research
• [Presentation] The Epigenetic Roles of LSD1+8a in Small Cell Lung Cancer. (2017)
  • Author(s): Wirawan A, Tajima K, Takahashi F, Hidayat M, Kanemaru R, Koinuma Y, Hayakawa D, Tajima M, Matsumoto N, Kanamori K, Takeda1 I, Kato M, Kobayashi I, Shimada N, Takahashi K.
  • Organizer: World Conference on Lung Cancer of the International Association for the Study of Lung Cancer (IASLC)
  • Int'l Joint Research
• [Presentation] Role of the ubiquitin ligase FBXW7/CDC4 in the maintenance of quiescent cancer stem cells resistant to gefitinib in EGFR mutation-positive non-small cell lung cancer (NSCLC). (2017)
  • Author(s): Hidayat M, Takahashi F, Tajima K, Nurwidya F, Wirawan A, Kanemaru R, Koinuma Y, Ihara H, Tajima M, Matsumoto N, Kanamori K, Takeda I, Haraguchi M, Hayakawa D, Ko R, Kato M, Shibayama R, Koyama R, Takahashi M, Shimada N, Takahashi K.
  • Organizer: World Conference on Lung Cancer of the International Association for the Study of Lung Cancer (IASLC)
  • Int'l Joint Research
• [Presentation] Histone deacetylase inhibition alters stem cell phenotype in gefitinib-resistant lung cancer cells with epidermal growth factor receptor mutation. (2017)
  • Author(s): Nurwidya F, Takahashi F, Hidayat M, Kobayashi I, Wirawan A, Kato M, Tajima K, Shimada N, Yunus, Takahashi K.
  • Organizer: World Conference on Lung Cancer of the International Association for the Study of Lung Cancer (IASLC)
  • Int'l Joint Research