cMET Activation and EGFR-Directed Therapy Resistance in Triple-Negative Breast Cancer.
cMET Activation and EGFR-Directed Therapy Resistance in Triple-Negative Breast Cancer.
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DOI：
10.7150/jca.9696
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发表时间：
2014
影响因子：
3.9
通讯作者：
Gonzalez-Angulo AM
中科院分区：
文献类型：
--
作者：
Sohn J;Liu S;Parinyanitikul N;Lee J;Hortobagyi GN;Mills GB;Ueno NT;Gonzalez-Angulo AM
背景：EGFR表达和通路激活在三阴性乳腺癌（TNBC）中很常见。然而，抗EGFR治疗在这些患者中并不有效。我们的目的是研究靶向MET在克服TNBC细胞系中对EGFR疗法的抗性中的功效。研究方法：用表皮生长因子（EGF）和肝细胞生长因子（HGF）刺激TNBC系（MDA-MB-468、HCC-1395和MDA-MB-231）和激素受体阳性乳腺癌系（T47 D）。然后用不同浓度的EGFR抑制剂（吉非替尼或西妥昔单抗）处理细胞系，有或没有MET酪氨酸激酶抑制剂（EMD 1214063）。通过MTS试验、软琼脂试验和基质胶试验测量增殖。用Calcusyn测量协同作用。用免疫印迹法检测蛋白质表达和信号传导。结果：EGF和HGF刺激后，MDA-MB-468和HCC-1395细胞中的配体-受体-下游信号通路被激活。在这些细胞系中，我们观察到EGFR和MET抑制剂组合时的协同作用。在各试验中观察到这些结果。在蛋白质印迹法中，联合治疗导致pAKT和pMAPK的废除，而单药治疗则没有。结论：我们的数据表明EGFR/MET双重抑制在TNBC中是协同的。靶向EGFR和MET受体两者可为TNBC提供有效的治疗策略。
Background: EGFR expression and pathway activation are common in triple-negative breast cancer (TNBC). However, anti-EGFR therapies have not been effective in these patients. We aimed to study the efficacy of targeting MET in overcoming resistance to EGFR therapy in TNBC cell lines. Methods: TNBC lines (MDA-MB-468, HCC-1395, and MDA-MB-231), and a hormone receptor-positive breast cancer line (T47D) were stimulated with epidermal growth factor (EGF) and hepatocyte growth factor (HGF). Lines were then treated with different concentrations of EGFR inhibitors (gefitinib or cetuximab), with or without a MET tyrosine kinase inhibitor (EMD 1214063). Proliferation was measured by MTS assay, in soft agar and with a matrigel assay. Synergy was measured with Calcusyn. Protein expression and signaling were examined with immunoblotting. Results: There was activation of ligand-receptor-downstream signaling pathways in MDA-MB-468 and HCC-1395 upon stimulation with EGF and HGF. In these cell lines, we observed synergism when combining EGFR and MET inhibitors. These results were observed across assays. In western blotting, combination therapy resulted in abrogation of pAKT and pMAPK while monotherapy did not. Conclusion: Our data demonstrate that dual EGFR/MET inhibition is synergistic in TNBC. Targeting both EGFR and MET receptors may provide an effective therapeutic strategy in TNBC.
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DOI：
10.1158/1078-0432.ccr-10-0568
发表时间：
2011-02-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Liska D;Chen CT;Bachleitner-Hofmann T;Christensen JG;Weiser MR
通讯作者：
Weiser MR
DOI：
10.1186/bcr1341
发表时间：
2005
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Reis-Filho JS;Milanezi F;Carvalho S;Simpson PT;Steele D;Savage K;Lambros MB;Pereira EM;Nesland JM;Lakhani SR;Schmitt FC
通讯作者：
Schmitt FC
影响因子：
11.2
作者：
Xu AM;Huang PH
通讯作者：
Huang PH
影响因子：
64.8
作者：
Sergina, Natalia V.;Rausch, Megan;Wang, Donghui;Blair, Jimmy;Hann, Byron;Shokat, Kevan M.;Moasser, Mark M.
通讯作者：
Moasser, Mark M.
影响因子：
45.3
作者：
Carey, Lisa A.;Rugo, Hope S.;Winer, Eric P.
通讯作者：
Winer, Eric P.