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.

本研究的目的是开发新疗法来克服 HGF 诱导的 EGFR-TKI 耐药性，并建立预测 HGF 诱导的肺癌耐药性的生物标志物。我们发现 HGF-Met 抑制剂可以在体外和体内克服 EGFR 突变型肺癌细胞中 HGF 诱导的 EGFR-TKI 耐药性。我们对临床标本的研究表明，在对 EGFR-TKI 具有获得性和内在耐药性的肿瘤中检测到高水平的 HGF，并且是最普遍的耐药因素，至少在患有 EGFR 突变肺癌的日本患者中是如此。我们进一步证明，EGFR-TKI 治疗前血浆中 HGF 的水平与肺癌的临床反应呈负相关。这些发现表明HGF是肺癌EGFR-TKI个体化治疗的重要靶点和生物标志物。

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

Hepatocyte growth factor as an inducer of EGFR-TKI resistance in lung cancer harboring EGFR activating mutations.

肝细胞生长因子作为具有 EGFR 激活突变的肺癌中 EGFR-TKI 耐药性的诱导剂。

• 发表时间: 2009
• 作者: Takuya Kuramoto;et al.;矢野聖二
• 通讯作者: 矢野聖二

Enhancement of osteoclastogenic activity in osteolytic prostate cancer cells by physical contact with osteoblasts.

• DOI: 10.1038/sj.bjc.6606070
• 发表时间: 2011-02-01
• 期刊: British journal of cancer
• 影响因子: 8.8

肝細胞増殖因子(HGF)はEGFR遺伝子変異T790Mを有する肺腺癌のirreversible EGFR阻害剤の耐性を誘導する

肝细胞生长因子（HGF）诱导EGFR基因突变T790M的肺腺癌对不可逆EGFR抑制剂产生耐药性

• 发表时间: 2009
• 作者: Kawarazaki H;Fujita T;et al.;山田忠明
• 通讯作者: 山田忠明

Epidemiological and clinical features of lung cancer patients from 1999 to 2009 in Tokushima Prefecture of Japan.

日本德岛县1999-2009年肺癌患者流行病学及临床特征

• 发表时间: 2010
• 期刊: J Med Invest
• 作者: Kanematsu T;Yano S;et al.
• 通讯作者: et al.