Development of translational research system to overcome refractory or rare lung cancer

• Project/Area Number: 17K09667
• 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: Keio University
• Principal Investigator: YASUDA Hiroyuki 慶應義塾大学, 医学部(信濃町), 講師 (70365261)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 肺癌 / 臨床検体 / 難治性肺癌 / 希少肺癌 / 遺伝子変異 / 分子標的治療薬 / 耐性化 / 癌

Outline of Final Research Achievements

Lung cancer is a leading cause of cancer related-deaths worldwide. Recent molecular characterizations of lung cancer contributed to the improvement of lung cancer patients. However, most advanced lung cancer patients die of lung cancer in several years. To improve the prognosis of lung cancer patients, further characterization of lung cancer is essential at a clinically relevant level. To this end, in this study, we aimed to develop a translational research system to overcome refractory or rare lung cancer. We developed a system to clarify the mechanisms of resistance to molecular target inhibitors in each patient. In addition, we have developed an in silico system to predict the drug sensitivity to molecular target inhibotrs for lung cancer patients harboring rare driver oncogene mutations. These findings will facilitate the improvement of precison medicine approaches in lung cancer.

Academic Significance and Societal Importance of the Research Achievements

近年肺癌領域ではがんゲノム医療が普及し、癌細胞の体細胞遺伝子変異に応じて患者毎に最適な治療薬を選択する個別化医療が可能になっている。しかし、このようにして最適な薬剤が判明した場合であっても多くの患者では肺癌細胞が薬剤に対する耐性を獲得し、患者予後を不良にしている。また、稀な遺伝子変異を有する肺癌に対しては最適な薬剤を選択する手法がなく医療現場における問題となっている。本研究では、患者毎に耐性化機序を解明するシステム、稀な肺癌に対してin silicoで最適な治療薬を選択するシステムを構築した。これら知見は、肺癌領域における個別化医療の質を向上させるものである。

Research Products

• [Journal Article] IGF2 Autocrine-Mediated IGF1R Activation Is a Clinically Relevant Mechanism of Osimertinib Resistance in Lung Cancer (2020)
  • Author(s): Manabe Tadashi、Yasuda Hiroyuki、Terai Hideki、Kagiwada Harumi、Hamamoto Junko、Ebisudani Toshiki、Kobayashi Keigo、Masuzawa Keita、Ikemura Shinnosuke、Kawada Ichiro、Hayashi Yuichiro、Fukui Kazuhiko、Horimoto Katsuhisa、Fukunaga Koichi、Soejima Kenzo
  • Journal Title: Molecular Cancer Research Volume: 印刷中 Issue: 4 Pages: 549-559
  • DOI: 10.1158/1541-7786.mcr-19-0956
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A phase II trial of induction of erlotinib followed by cytotoxic chemotherapy for EGFR mutation-positive non-squamous non-small cell lung cancer patients. (2019)
  • Author(s): Tani T, Naoki K, Yasuda H, Arai D, Ishioka K, Ohgino K, Yoda S, Nakayama S, Satomi R, Terai H, Ikemura S, Sato T, Soejima K.
  • Journal Title: Cancer Chemother Pharmacol Volume: 84 Issue: 5 Pages: 1065-1071
  • DOI: 10.1007/s00280-019-03934-y
  • Peer Reviewed
• [Journal Article] TAS6417/CLN-081 Is a Pan-Mutation-Selective EGFR Tyrosine Kinase Inhibitor with a Broad Spectrum of Preclinical Activity against Clinically Relevant EGFR Mutations. (2019)
  • Author(s): Udagawa H, Hasako S, Ohashi A, Fujioka R, Hakozaki Y, Shibuya M, Abe N, Komori T, Haruma T, Terasaka M, Fujita R, Hashimoto A, Funabashi K, Yasuda H, Miyadera K, Goto K, Costa DB, Kobayashi SS.
  • Journal Title: Mol Cancer Res Volume: 17(11) Issue: 11 Pages: 2233-2243
  • DOI: 10.1158/1541-7786.mcr-19-0419
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Monomer Preference of EGFR Tyrosine Kinase Inhibitors Influences the Synergistic Efficacy of Combination Therapy with Cetuximab. (2019)
  • Author(s): Oashi A, Yasuda H, Kobayashi K, Tani T, Hamamoto J, Masuzawa K, Manabe T, Terai H, Ikemura S, Kawada I, Naoki K, Soejima K
  • Journal Title: Mol Cancer Ther Volume: 18 Issue: 9 Pages: 1593-1601
  • DOI: 10.1158/1535-7163.mct-18-1036
  • Peer Reviewed
• [Journal Article] Effect of FGF/FGFR pathway blocking on lung adenocarcinoma and its cancer-associated fibroblasts. (2019)
  • Author(s): Hegab AE, Ozaki M, Kameyama N, Gao J, Kagawa S, Yasuda H, Soejima K, Yin Y, Guzy RD, Nakamura Y, Ornitz DM, Betsuyaku T.
  • Journal Title: J Pathol Volume: 249 Issue: 2 Pages: 193-205
  • DOI: 10.1002/path.5290
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Molecular dynamics simulation-guided drug sensitivity prediction for lung cancer with rare EGFR mutations (2019)
  • Author(s): Ikemura S, Yasuda H, Matsumoto S, Kamada M, Hamamoto J, Masuzawa K, Kobayashi K, Manabe T, Arai D, Nakachi I, Kawada I, Ishioka K, Nakamura M, Namkoong H, Naoki K, Ono F, Araki M, Kanada R, Ma B, Hayashi Y, Mimaki S, Yoh K, Kobayashi SS, Kohno T, Okuno Y, Goto K, Tsuchihara K, Soejima K.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: Epub ahead of print Issue: 20 Pages: 10025-10030
  • DOI: 10.1073/pnas.1819430116
  • NAID: 120006799239
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Efficacy of afatinib or osimertinib plus cetuximab combination therapy for non-small-cell lung cancer with EGFR exon 20 insertion mutations. (2019)
  • Author(s): Hasegawa H, Yasuda H, Hamamoto J, Masuzawa K, Tani T, Nukaga S, Hirano T, Kobayashi K, Manabe T, Terai H, Ikemura S, Kawada I, Naoki K, Soejima K.
  • Journal Title: Lung Cancer Volume: 127 Pages: 146-152
  • Peer Reviewed
• [Journal Article] Efficacy of afatinib or osimertinib plus cetuximab combination therapy for non-small-cell lung cancer with EGFR exon 20 insertion mutations (2019)
  • Author(s): Hasegawa H, Yasuda H, Hamamoto J, Masuzawa K, Tani T, Nukaga S, Hirano T, Kobayashi K, Manabe T, Terai H, Ikemura S, Kawada I, Naoki K, Soejima K.
  • Journal Title: Lung Cancer Volume: 127 Pages: 146-52
  • DOI: 10.1016/j.lungcan.2018.11.039
  • Peer Reviewed
• [Journal Article] Pharmacological and Structural Characterizations of Naquotinib, a Novel Third-Generation EGFR Tyrosine Kinase Inhibitor, in EGFR-Mutated Non-Small Cell Lung Cancer. (2018)
  • Author(s): Hirano T, Yasuda H, Hamamoto J, Nukaga S, Masuzawa K, Kawada I, Naoki K, Niimi T, Mimasu S, Sakagami H, Soejima K, Betsuyaku T
  • Journal Title: Mol Cancer Ther Volume: 17(4) Issue: 4 Pages: 740-750
  • DOI: 10.1158/1535-7163.mct-17-1033
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Intermittent Exposure to Cigarette Smoke Increases Lung Tumors and the Severity of Emphysema More Than Continuous Exposure. (2018)
  • Author(s): Kameyama N, Chubachi S, Hegab AE, Yasuda H, Kagawa S, Tsutsumi A, Fukunaga K, Shimoda M, Kanai Y, Soejima K, Betsuyaku T.
  • Journal Title: Am J Respir Cell Mol Biol. Volume: Epub ahead of print Issue: 2 Pages: 179-188
  • DOI: 10.1165/rcmb.2017-0375oc
  • Peer Reviewed
• [Journal Article] Characterization of the efficacies of osimertinib and nazartinib against cells expressing clinically relevant epidermal growth factor receptor mutations. (2017)
  • Author(s): Masuzawa K, Yasuda H, Hamamoto J, Nukaga S, Hirano T, Kawada I, Naoki K, Soejima K, Betsuyaku T.
  • Journal Title: Oncotarget. Volume: 8(62) Issue: 62 Pages: 105479-105491
  • DOI: 10.18632/oncotarget.22297
  • Peer Reviewed / Open Access
• [Journal Article] Non-small cell lung cancer PC-9 cells exhibit increased sensitivity to gemcitabine and vinorelbine upon acquiring resistance to EGFR-tyrosine kinase inhibitors. (2017)
  • Author(s): Hamamoto J, Yasuda H, Aizawa K, Nishino M, Nukaga S, Hirano T, Kawada I, Naoki K, Betsuyaku T, Soejima K.
  • Journal Title: Oncol Lett. Volume: 14(3) Issue: 3 Pages: 3559-3565
  • DOI: 10.3892/ol.2017.6591
  • Peer Reviewed