Development of potential therapy using histone modifying enzyme inhibitor to overcome drug resistance of non-small lung cancer
Project/Area Number |
17K09639
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Respiratory organ internal medicine
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Research Institution | Hokkaido University |
Principal Investigator |
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Project Period (FY) |
2017-04-01 – 2020-03-31
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Project Status |
Completed (Fiscal Year 2019)
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Budget Amount *help |
¥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)
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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.
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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。
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Report
(4 results)
Research Products
(13 results)
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[Journal Article] Evaluating the immunoproteasome as a potential therapeutic target in cisplatin-resistant small cell and non-small cell lung cancer2020
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
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Journal Title
Cancer Chemother Pharmacol
Volume: in print
Issue: 5
Pages: 843-853
DOI
NAID
Related Report
Peer Reviewed
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[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
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Journal Title
International Journal of Clinical Oncology
Volume: 23
Issue: 6
Pages: 1060-1069
DOI
NAID
Related Report
Peer Reviewed
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[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.
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Journal Title
ESMO Open
Volume: 3(2)
Issue: 2
Pages: e000313-e000313
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[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
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Journal Title
Cancer Chemother Pharmacol
Volume: 80
Issue: 5
Pages: 955-963
DOI
NAID
Related Report
Peer Reviewed / Int'l Joint Research
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[Presentation] A phase II study of trastuzumab monotherapy in pretreated patients with non-small cell lung cancers (NSCLCs) harboring HER2 alterations: HOT1303-B trial2018
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
Related Report
Int'l Joint Research
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