Development of individual therapy for overcoming HGF-induced molecular targeted drug-resistance in EGFR-mutant lung cancer

开发个体化疗法以克服 EGFR 突变型肺癌中 HGF 诱导的分子靶向耐药性

• 批准号: 21390256
• 负责人: YANO Seiji
• 金额: $ 11.4万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21390256/
• 关键词: 肺癌; EGFR-TKI; 薬剤耐性; HGF; Met; EGFR遺伝子変異; バイオマーカー; PI3K; 公子標的治療; 肝細胞増殖因子; MET; 線維芽細胞; 上皮成長因子受容体; ゲフィチニブ

The purpose of this study was to develop novel therapy for overcoming HGF-induced EGFR-TKI resistance and establish biomarkers which predict the HGF-induced resistance in lung cancer. We found that inhibitors of HGF-Met could overcome HGF-induced EGFR-TKI resistance in EGFR mutant lung cancer cells in vitro and in vivo. Our study with clinical specimens reveled that high levels of HGF were detected in tumors with acquired and intrinsic resistance to EGFR-TKI and was the most prevalent factor for resistance, at least in Japanese patients with EGFR-mutant lung cancer. We further demonstrated that levels of HGF in plasma before EGFR-TKI treatment inversely correlated with clinical response in lung cancer. These finding suggest that HGF is the important target and biomarker of individual therapy with EGFR-TKI in lung cancer.

这项研究的目的是开发用于克服HGF诱导的EGFR-TKI耐药性并建立生物标志物的新型疗法，以预测HGF诱导的肺癌耐药性。我们发现，HGF-MET的抑制剂可以在体外和体内克服HGF诱导的EGFR-TKI耐药性。我们对临床标本的研究始终是在获得EGFR-TKI的肿瘤中检测到高水平的HGF，并且至少在日本EGFR-突变肺癌患者中是耐药性最普遍的因素。我们进一步证明，在EGFR-TKI治疗之前，血浆中的HGF水平与肺癌的临床反应成反比。这些发现表明，HGF是肺癌中EGFR-TKI的个体疗法的重要靶标和生物标志物。

项目成果

Gender difference in bone metastasis of human small cell lung cancer, SBC-5 cells in natural killer-cell depleted severe combined immunodeficient mice

• DOI: 10.1007/s10585-010-9333-0
• 发表时间: 2010-05
• 期刊: Clinical & Experimental Metastasis
• 影响因子: 4
• 作者: Satoshi Sakaguchi;H. Goto;M. Hanibuchi;Shinsaku Otsuka;H. Ogino;S. Kakiuchi;H. Uehara;S. Yano;Y. Nishioka;S. Sone

The EGFR Ligands Amphiregulin and Heparin-Binding EGF-like Growth Factor Promote Peritoneal Carcinomatosis in CXCR4-Expressing Gastric Cancer

• DOI: 10.1158/1078-0432.ccr-10-2475
• 发表时间: 2011-06-01
• 期刊: CLINICAL CANCER RESEARCH
• 影响因子: 11.5
• 作者: Yasumoto, Kazuo;Yamada, Tadaaki;Yano, Seiji
• 通讯作者: Yano, Seiji

Hepatocyte Growth Factor Expression in EGFR Mutant Lung Cancer with Intrinsic and Acquired Resistance to Tyrosine Kinase Inhibitors in a Japanese Cohort

• DOI: 10.1097/jto.0b013e31823ab0dd
• 发表时间: 2011-12-01
• 期刊: JOURNAL OF THORACIC ONCOLOGY
• 影响因子: 20.4
• 作者: Yano, Seiji;Yamada, Tadaaki;Noguchi, Masayuki
• 通讯作者: Noguchi, Masayuki

肺がんの分子標的薬耐性と微小環境.(招待講演)

肺癌的分子靶向耐药性与微环境（特邀报告）。

• 发表时间: 2009
• 作者: Xu B;Zhang Y;Zhao Z;Yoshida Y;Magdeldin S;Fujinaka H;Ismail TA;Yaoita E;Yamamoto T;Nangaku M;森建文;Ishii H;矢野聖二
• 通讯作者: 矢野聖二

HGFによるEGFR-TKI耐性の分子機構解明とその克服に向けた研究(篠井・河合賞受賞講演)

阐明HGF诱导的EGFR-TKI耐药性的分子机制及克服该耐药性的研究（筱井河合奖获奖演讲）

• 发表时间: 2010
• 作者: Nagase M;Ayuzawa N;Kawarazaki W;Ishizawa K;Ueda K;Yoshida S;Fujita T.;矢野聖二
• 通讯作者: 矢野聖二