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

2019 Fiscal Year Final Research Report

• 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
• 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

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.

Free Research Field

腫瘍内科学、がんゲノム医療学

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。