Development of potential therapy using histone modifying enzyme inhibitor to overcome drug resistance of non-small lung cancer

• Project/Area Number: 17K09639
• 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: Hokkaido University
• Principal Investigator: Kinoshita Ichiro 北海道大学, 大学病院, 教授 (40343008)
• 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: ヒストン修飾 / 脱メチル化酵素 / JARID1 / PBIT / 肺癌 / EGFR / 薬剤耐性 / エピゲノム / ヒストン修飾酵素 / 分子標的薬 / 抗癌薬耐性 / EZH2

Outline of Final Research Achievements

PBIT, a small molecule inhibitor of the JARID1a/b histone demethylases, restored the drug sensitivity of multiple drug-resistant persister cells that were established from NSCLC lines. In addition, PBIT prevented the expansion of EGFR-TKI-resistant persisters through modifying secretomes from EGFR-TKI sensitive cells by inhibiting downregulation of FRA1 expression via prevention of decreased H3K4me3 levels at FRA1 promoter regions. These findings suggest the potential efficacy of PBIT as a novel therapeutic strategy for lung cancer and have particularly important implications in restoring drug resistance in NSCLC, given that patients with activating EGFR mutations who are given EGFR-targeted therapies commonly develop resistance.

Academic Significance and Societal Importance of the Research Achievements

ドライバー遺伝子変異を標的にした分子標的治療の進歩が著しいが、肺癌をはじめとする固形癌では最終的に薬剤耐性が出現し、進行肺癌の克服のためには新たなブレイクスルーが必要である。ヒストン脱メチル化酵素JARID1a/b阻害薬は、癌幹様細胞の減少に加え、抗がん薬感受性細胞の分泌シグナルのネットワーク（セクレトーム）を変化させることにより、抗がん薬耐性化を克服することが示され、肺癌の新たな治療戦略となる可能性がある。

Research Products

• [Journal Article] Evaluating the immunoproteasome as a potential therapeutic target in cisplatin-resistant small cell and non-small cell lung cancer (2020)
  • Author(s): Shoji T, Kikuchi E, Kikuchi J, Takashima Y, Furuta M, Takahashi H, Tsuji K, Maeda M, Kinoshita I, Dosaka-Akita H, Sakakibara-Konishi J, Konno S
  • Journal Title: Cancer Chemother Pharmacol Volume: in print Issue: 5 Pages: 843-853
  • DOI: 10.1007/s00280-020-04061-9
  • NAID: 120007032615
  • Peer Reviewed
• [Journal Article] Bromodomain and extraterminal domain inhibition synergizes with WEE1‐inhibitor AZD1775 effect by impairing nonhomologous end joining and enhancing DNA damage in nonsmall cell lung cancer (2020)
  • Author(s): Takashima Yuta、Kikuchi Eiki、Kikuchi Junko、Suzuki Motofumi、Kikuchi Hajime、Maeda Makie、Shoji Tetsuaki、Furuta Megumi、Kinoshita Ichiro、Dosaka‐Akita Hirotoshi、Sakakibara‐Konishi Jun、Konno Satoshi
  • Journal Title: International Journal of Cancer Volume: 146 Issue: 4 Pages: 1114-1124
  • DOI: 10.1002/ijc.32515
  • NAID: 120006958367
  • Peer Reviewed
• [Journal Article] DLL3 regulates the migration and invasion of small cell lung cancer by modulating Snail (2019)
  • Author(s): Furuta Megumi、Kikuchi Hajime、Shoji Tetsuaki、Takashima Yuta、Kikuchi Eiki、Kikuchi Junko、Kinoshita Ichiro、Dosaka‐Akita Hirotoshi、Sakakibara‐Konishi Jun
  • Journal Title: Cancer Science Volume: in print Issue: 5 Pages: 1599-1608
  • DOI: 10.1111/cas.13997
  • Peer Reviewed / Open Access
• [Journal Article] Numb has distinct function in lung adenocarcinoma and squamous cell carcinoma (2018)
  • Author(s): Kikuchi Hajime、Sakakibara-Konishi Jun、Furuta Megumi、Kikuchi Eiki、Kikuchi Junko、Oizumi Satoshi、Hida Yasuhiro、Kaga Kichizo、Kinoshita Ichiro、Dosaka-Akita Hirotoshi、Nishimura Masaharu
  • Journal Title: Oncotarget Volume: 9 Issue: 50 Pages: 29379-29391
  • DOI: 10.18632/oncotarget.25585
  • Peer Reviewed
• [Journal Article] A phase II study of carboplatin, pemetrexed, and bevacizumab followed by erlotinib and bevacizumab maintenance for non-squamous non-small cell lung cancer with wild-type EGFR (HOT1101) (2018)
  • Author(s): Takashina T, Asahina H, Oizumi S, Yamada N, Harada M, Takamura K, Yokouchi H, Harada T, Honjo O, Ogi T, Morikawa N, Kinoshita I, Honda R, Nakano K, Kanazawa K, Amano T, Dosaka-Akita H, Isobe H, Nishimura M
  • Journal Title: International Journal of Clinical Oncology Volume: 23 Issue: 6 Pages: 1060-1069
  • DOI: 10.1007/s10147-018-1318-z
  • NAID: 120006651802
  • Peer Reviewed
• [Journal Article] Clinicopathologic Features and Immune Microenvironment of Non?Small-cell Lung Cancer With Primary Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (2018)
  • Author(s): Takashima Yuta、Sakakibara-Konishi Jun、Hatanaka Yutaka、Hatanaka Kanako C.、Ohhara Yoshihito、Oizumi Satoshi、Hida Yasuhiro、Kaga Kichizo、Kinoshita Ichiro、Dosaka-Akita Hirotoshi、Matsuno Yoshihiro、Nishimura Masaharu
  • Journal Title: Clinical Lung Cancer Volume: 19 Issue: 4 Pages: 352-359
  • DOI: 10.1016/j.cllc.2018.02.004
  • NAID: 120006649179
  • Peer Reviewed
• [Journal Article] Updated survival outcomes of NEJ005/TCOG0902: a randomised phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations. (2018)
  • Author(s): Oizumi S, Sugawara S, Minato K, Harada T, Inoue A, Fujita Y, Maemondo M, Watanabe S, Ito K, Gemma A, Demura Y, Fukumoto S, Isobe H, Kinoshita I, Morita S, Kobayashi K, Hagiwara K, Aiba K, Nukiwa T.
  • Journal Title: ESMO Open Volume: 3(2) Issue: 2 Pages: e000313-e000313
  • DOI: 10.1136/esmoopen-2017-000313
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A randomized phase II trial of erlotinib vs. S-1 as a third- or fourth-line therapy for patients with wild-type EGFR non-small cell lung cancer (HOT1002) (2017)
  • Author(s): Ikezawa Y, Asahina H, Oizumi S, Watanabe M, Takamura K, Kawai Y, Yamada N, Harada T, Kinoshita I, Fujita Y, Miyauchi E, Ogi T, Amano T, Furuta M, Sakakibara-Konishi J, Nishihara H, Dosaka-Akita H, Isobe H, Nishimura M; Hokkaido Lung Cancer Clinical Study Group
  • Journal Title: Cancer Chemother Pharmacol Volume: 80 Issue: 5 Pages: 955-963
  • DOI: 10.1007/s00280-017-3432-4
  • NAID: 120006533131
  • Peer Reviewed / Int'l Joint Research
• [Presentation] ヒストン脱メチル化酵素JARID1阻害薬による非小細胞肺癌細胞のEGFR-TKI耐性化の抑制 (2019)
  • Author(s): 有賀 伸, 木下 一郎, 菊地 順子, 清水 康, 秋田 弘俊,
  • Organizer: 第60回日本肺癌学会学術集会
• [Presentation] JARID1 family inhibitor reduces generation of drug resistant EGFR-mutation positive lung cancer cells (2019)
  • Author(s): Ariga S, Kinoshita I, Kikuchi J, Shimizu S, Dosaka-Akita H
  • Organizer: 110th Annual Meeting of the American Association for Cancer Research
  • Int'l Joint Research
• [Presentation] JARID1ファミリー阻害薬はEGFR変異陽性肺癌細胞株の薬剤耐性化を緩和する (2018)
  • Author(s): 有賀 伸, 木下 一郎, 菊地 順子, 清水 康, 秋田 弘俊
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] A phase II study of trastuzumab monotherapy in pretreated patients with non-small cell lung cancers (NSCLCs) harboring HER2 alterations: HOT1303-B trial (2018)
  • Author(s): Kinoshita I, Goda T, Watanabe K, Maemondo M, Oizumi S, Amano T, Hatanaka Y, Matsuno Y, Nishihara H, Asahina H, Harada T, Goto K, Isobe H, Nishimura M, Dosaka-Akita H
  • Organizer: European Society for Medical Oncology 2018 Congress
  • Int'l Joint Research
• [Presentation] JARIDファミリー阻害薬の非小細胞肺癌細胞株に対する効果 (2017)
  • Author(s): 有賀伸、木下一郎、菊地順子、清水康、秋田弘俊
  • Organizer: 第58回日本肺癌学会学術集会