Role of quiescent cancer stem cells in the gefitinib resistance in EGFR mutation positive non-small cell lung cancer

• Project/Area Number: 15K09230
• 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 Kazuhisa 順天堂大学, 医学部, 教授 (80245711)
• Co-Investigator(Kenkyū-buntansha): 高橋 史行 順天堂大学, 医学部, 准教授 (70327823)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 薬剤耐性 / 癌幹細胞 / 静止期 / 肺癌 / 非小細胞肺癌 / Gefitinib / EGFR-TKI耐性 / 肺癌幹細胞 / Gefitinib耐性

Outline of Final Research Achievements

Several recent studies suggest that cancer stem cells (CSCs) are involved in intrinsic resistance to cancer treatment. Maintenance of quiescence is crucial for establishing resistance of CSCs to cancer therapeutics. In this study, we developed gefitinib-resistant persisters (GRPs) from two EGFR-mutant non-small cell lung cancer (NSCLC) cell lines, PC9 and HCC827 by treatment with a high concentration of gefitinib. The GRPs from both PC9 and HCC827 cells expressed high level of lung CSC marker CD133 and gene X that is involved in the maintenance of quiescence of CSCs. Cell cycle analysis demonstrated that the majority of GRPs existed in the G0/G1 phase. Knockdown of the gene X significantly reduced the cell number of CD133-positive GRPs and reversed the cell population in the G0/G1-phase. These findings suggest that the maintenance of quiescence is important in gefitinib-resistant lung CSCs in EGFR mutation-positive NSCLC.

Academic Significance and Societal Importance of the Research Achievements

現在、肺癌は日本のみならず世界でも癌による死亡原因の第1位を占めている。とくに進行肺癌の予後は極めて不良であり、本研究によりGefitinib耐性機序における肺癌幹細胞の静止期維持機構の重要性が認識され、静止期制御分子の抑制や阻害剤を用いた癌幹細胞・静止期制御の有用性がより立証されれば、将来的に非小細胞肺癌におけるEGFR-TKI耐性克服の重要なオプションの一つとなり、進行肺癌の予後改善につながる可能性がある。

Research Products

• [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] 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] Prognostic Factors and Efficacy of First-Line Chemotherapy in Patients with Advanced Thymic Carcinoma (2018)
  • Author(s): Ko R, Shukuya T, Okuma Y, Tateishi K, Imai H, Iwasawa S, Miyauchi E, Fujiwara A, Sugiyama T, Azuma K, Muraki K, Yamasaki M, Tanaka H, Takashima Y, Soda S, Ishimoto O, Koyama N, Morita S, Kobayashi K, Nukiwa T, Takahashi K; North East Japan Study Group.
  • Journal Title: Oncologist Volume: unknown Issue: 10 Pages: 1210-1217
  • DOI: 10.1634/theoncologist.2017-0586
  • Peer Reviewed
• [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] Comparison of the Analytical Performance Between cobas EGFR Assay and PCR-Clamp Method in the Detection of EGFR Mutations in Japanese Non-Small Cell Lung Cancer Patients (2017)
  • Author(s): Ai Tomohiko、Yuri Maiko、Tabe Yoko、Kakimoto Atsushi、Morishita Soji、Tsuchiya Koji、Takamochi Kazuya、Kodama Yuzo、Takahashi Fumiyuki、Shigeki Misawa、Horii Takashi、Suzuki Kenji、Takahashi Kazuhisa、Miida Takashi、Ohsaka Akimichi
  • Journal Title: Clinical Laboratory Volume: 63 Issue: 05+06/2017 Pages: 1021-1026
  • DOI: 10.7754/clin.lab.2017.161223
  • Peer Reviewed
• [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
• [Journal Article] Oct4 plays a crucial role in the maintenance of gefitinib-resistant lung cancer stem cells. (2016)
  • Author(s): Kobayashi I, Takahashi F, Nurwidya F, Nara T, Hashimoto M, Murakami A,
  • Journal Title: Biochem Biophys Res Commun Volume: in press Issue: 1 Pages: 125-132
  • DOI: 10.1016/j.bbrc.2016.03.064
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cerebral infarction in advanced non-small cell lung cancer. (2016)
  • Author(s): Kato M, Takahashi F, Takahashi K, et al.
  • Journal Title: BMC Cancer Volume: 10 Issue: 1 Pages: 203-203
  • DOI: 10.1186/s12885-016-2233-1
  • Peer Reviewed
• [Journal Article] Haploinsufficiency of the folliculin gene leads to impaired functions of lung fibroblasts in patients with Birt-Hogg-Dube syndrome. (2016)
  • Author(s): Hoshika Y, Takahashi F, Takahashi K, et al.
  • Journal Title: Physiological Reports Volume: 4 Pages: 13025-13025
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Chemotherapy induced microRNA-125/HER2 pathway as a novel therapeutic target for trastuzumab-mediated cellular cytotoxicity in small-cell lung cancer. (2015)
  • Author(s): Yagishita S, Takahashi F, Takahashi K, et al.
  • Journal Title: Mol Cancer Ther Volume: 14 Issue: 6 Pages: 1414-23
  • DOI: 10.1158/1535-7163.mct-14-0625
  • Peer Reviewed
• [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 Role of LSD1/KDM1 Isoform LSD1+8a in Small Cell Lung Carcinoma (2017)
  • Author(s): Ihara H, Takahashi F, Takahashi K, et al.
  • Organizer: Congress of American Thoracic Society (ATS)
  • Place of Presentation: Washington
  • Year and Date: 2017-05-19
  • Int'l Joint Research
• [Presentation] Role of quiescent cancer stem cells in the gefitinib resistance in EGFR mutation positive non-small cell lung cancer (NSCLC). (2017)
  • Author(s): Hidayat M, Takahashi F, Takahashi K, et al.
  • Organizer: Congress of the Asian Pacific Society of Respirology (APSR)
  • 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, Takahashi K, et al.
  • Organizer: World Conference on Lung Cancer of the International Association for the Study of Lung Cancer (IASLC)
  • Int'l Joint Research
• [Presentation] Knockdown of Oct4 reverses epithelial-mesenchymal transition induced by insulin-like growth factor 1 in lung cancer. (2016)
  • Author(s): Nurwidya F, Takahashi F, Takahashi K. et al.
  • Organizer: Asian Pacific Society of Respirology (APSR)
  • Place of Presentation: Bangkok
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Cerebral infarction in advanced non-small cell lung cancer (2015)
  • Author(s): Kato M, Takahashi F, Takahashi K, et al.
  • Organizer: Asian Pacific Society of Respirology
  • Place of Presentation: Kuala Lumpur
  • Year and Date: 2015-12-03
  • Int'l Joint Research
• [Presentation] Role of POU5F1 in gefitinib resistance in EGFR-mutant non-small cell lung cancer (NSCLC) (2015)
  • Author(s): Kobayashi I, Takahashi F, Takahashi K, et al.
  • Organizer: 日本呼吸器学会総会（英語ポスター発表）
  • Place of Presentation: 東京
  • Year and Date: 2015-04-17