晚期NSCLC靶向和化疗方案选择的几个问题

老马 · 发表于 2013-8-6 00:18:25

PI3K/Akt pathway inhibition could overcome HGF-mediated
resistance to EGFR-TKIs (Donev IS, CCR 2011)
1. 可以联用HGF单抗
2. 可以联用PI3K药，比如BKM120.

今年夏天2010 · 发表于 2013-8-6 12:27:26

老马发表于 2013-8-6 00:18

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PI3K/Akt pathway inhibition could overcome HGF-mediated
resistance to EGFR-TKIs (Donev IS, CCR 201 ...

学习了，谢谢！

老马 · 发表于 2013-8-6 19:07:36

本帖最后由老马于 2013-8-6 19:40 编辑

Clin Cancer Res. 2012 Mar 15;18(6):1663-71. doi: 10.1158/1078-0432.CCR-11-1171. Epub 2012 Feb 8.
Met kinase inhibitor E7050 reverses three different mechanisms of hepatocyte growth factor-induced tyrosine kinase inhibitor resistance in EGFR mutant lung cancer.
Wang W, Li Q, Takeuchi S, Yamada T, Koizumi H, Nakamura T, Matsumoto K, Mukaida N, Nishioka Y, Sone S, Nakagawa T, Uenaka T, Yano S.
Source
Kanazawa University, Kanazawa, Ishikawa, Japan.

Abstract
PURPOSE:
Hepatocyte growth factor (HGF) induces resistance to reversible and irreversible epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) in EGFR mutant lung cancer cells by activating Met and the downstream phosphoinositide 3-kinase (PI3K)/Akt pathway. Moreover, continuous exposure to HGF accelerates the emergence of EGFR-TKI-resistant clones. We assayed whether a new Met kinase inhibitor, E7050, which is currently being evaluated in clinical trials, could overcome these three mechanisms of resistance to EGFR-TKIs.
EXPERIMENTAL DESIGN:
The effects of E7050 on HGF-induced resistance to reversible (gefitinib), irreversible (BIBW2992), and mutant-selective (WZ4002) EGFR-TKIs were determined using the EGFR mutant human lung cancer cell lines PC-9 and HCC827 with an exon 19 deletion and H1975 with an T790M secondary mutation. PC-9 cells were mixed with HGF-producing fibroblasts, MRC-5 cells, and subcutaneously inoculated into severe combined immunodeficient mice, and the therapeutic effects of E7050 plus gefitinib were assayed.
RESULTS:
E7050 circumvented resistance to all of the reversible, irreversible, and mutant-selective EGFR-TKIs induced by exogenous and/or endogenous HGF in EGFR mutant lung cancer cell lines, by blocking the Met/Gab1/PI3K/Akt pathway in vitro. E7050 also prevented the emergence of gefitinib-resistant HCC827 cells induced by continuous exposure to HGF. In the in vivo model, E7050 plus gefitinib resulted in marked regression of tumor growth associated with inhibition of Akt phosphorylation in cancer cells.
CONCLUSIONS:
A new Met kinase inhibitor, E7050, reverses the three HGF-induced mechanisms of gefitinib resistance, suggesting that E7050 may overcome HGF-induced resistance to gefitinib and next-generation EGFR-TKIs.

Met kinase inhibitor E7050 reverses three different mechanisms of hepatocyte gro.pdf (805.33 KB, 下载次数: 159)

老马 · 发表于 2013-8-6 19:09:33

老马 · 发表于 2013-8-6 19:15:54

本帖最后由老马于 2013-8-6 19:18 编辑

Golvatinib (also known as E7050) is a highly potent, small molecule ATP-competitive inhibitor of the c-Met receptor tyrosine kinase and multiple members of the Eph receptor family. c-Met and VEGFR-2 play important roles in tumor cell growth, migration and angiogenesis. Golvatinib (E7050) inhibits the activities of both c-Met and VEGFR-2, which may inhibit tumor cell growth and survival of tumor cells that overexpress these receptor tyrosine kinases. In vitro, Golvatinib (E7050) circumvented resistance to all of the reversible, irreversible, and mutant-selective EGFR-TKIs induced by exogenous and/or endogenous HGF in EGFR mutant lung cancer cell lines, by blocking the Met/Gab1/PI3K/Akt pathway. Golvatinib (E7050) plus gefitinib resulted in marked regression of tumor growth associated with inhibition of Akt phosphorylation in cancer cells in the in vivo model. Golvatinib is currently under evaluation in a phase I clinical trial, it may overcome HGF-induced resistance to gefitinib and next-generation EGFR-TKIs.

老马 · 发表于 2013-8-6 19:30:49

图1 在NSCLC中，对表皮和肝细胞生长因子和其酪氨酸激酶受体特有分子通路，作为多药靶点。EGFR配体和HGF结合至其特异性跨膜受体和，通过位于细胞内激酶结构区内关键酪氨酸残基的自身磷酸化和随后TK活性的激活，触发分子机制向下游细胞内发信号。RascRafMEKERK；PI- 3KAkt-PKBmTOR和STATs是涉及的主要通路。这些信号可影响细胞生命的关键方面包括增殖，生存，凋亡，迁移，血管生成和其他基本过程。在窗内指示在临床前和临床水平在NSCLC治疗所用主要受试化合物，及其奇特分子靶点。靶向某些关键步骤化合物以斜体表示 – 在上述通路中GF/GF-RTK结合的下游，一般在真核细胞中发现和在某些人肿瘤评价但在NSCLC尚未评价。缩写：EGF/EGFR，表皮生长因子/表皮生长因子受体；HGF，肝细胞生长因子；c-MetR，蛋白上皮间质转换因子；TK，酪氨酸激酶；P，磷；Ras，GTPGDPase蛋白；Raf，原癌基因丝氨酸/苏氨酸蛋白激酶；MAP3K，MAP2K(MEK)和MAPK，有丝分裂原-活化的蛋白激酶；Erk1/2，细胞外信号-调节激酶；PI-3K，磷脂酰肌醇-3激酶；Akt，1，2，3 丝氨酸/苏氨酸蛋白激酶；mTOR，哺乳动物雷帕霉素靶蛋白；STAT，信号转导和转录蛋白的激活剂。

老马 · 发表于 2013-8-6 20:03:32

今年夏天2010 · 发表于 2013-8-6 20:58:49

老马发表于 2013-8-6 19:15

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Golvatinib (also known as E7050) is a highly potent, small molecule ATP-competitive inhibitor of the ...

马哥, 又一新药, 也许病友们能等得到用上这药吧? >_< 这个药似乎比120还强大? 请指教.

老马 · 发表于 2013-8-6 21:23:25

Indeed, previous studies reported that the level of Met phosphorylation was higher in HCC827 cells than in other EGFRmutant cell lines .
19突变的病人发生cmet扩增的比例更高。