Strong EGFR signaling in cell line models of ERBB2-amplified breast cancer attenuates response towards ERBB2-targeting drugs.
Strong EGFR signaling in cell line models of ERBB2-amplified breast cancer attenuates response towards ERBB2-targeting drugs.
复制标题
DOI：
10.1038/oncsis.2012.16
复制
发表时间：
2012-07-02
期刊：
影响因子：
6.2
通讯作者：
Korf, U.
中科院分区：
文献类型：
--
作者：
Henjes, F.;Bender, C.;von der Heyde, S.;Braun, L.;Mannsperger, H. A.;Schmidt, C.;Wiemann, S.;Hasmann, M.;Aulmann, S.;Beissbarth, T.;Korf, U.
提高靶向癌症治疗的疗效需要鉴定适用于患者分层的稳健生物标志物。本研究的重点是鉴定导致抗ERBB 2靶向治疗抗体曲妥珠单抗和帕妥珠单抗耐药的分子机制，目前用于治疗ERBB 2扩增的乳腺癌患者。免疫组化和临床数据进行了评价，并产生了证据的存在ERBB 2扩增的乳腺癌与高水平的表皮生长因子受体（EGFR）表达作为一个单独的肿瘤实体。由于原癌基因EGFR在蛋白质水平上与ERBB 2紧密相互作用，因此高水平EGFR表达可能导致对ERBB 2靶向治疗耐药的假设得到了实验验证。选择SKBR 3和HCC 1954细胞作为EGFR-高/ERBB 2-扩增的乳腺癌的模型系统，并分别暴露于曲妥珠单抗、帕妥珠单抗和厄洛替尼，以及组合。在细胞活力测定中和使用反相蛋白质阵列在蛋白质组学水平上定量药物影响。磷蛋白动力学显示，在SKBR 3细胞中暴露于曲妥珠单抗、帕妥珠单抗或两种抗体的共同应用后，AKT信号传导显著下调，但对ERK 1/2、RB或RPS 6磷酸化没有伴随影响。另一方面，在EGFR和ERBB 2共抑制后，SKBR 3细胞中的信号传导完全下调。HCC 1954细胞中的抑制作用由单独的厄洛替尼驱动，并且在与帕妥珠单抗和曲妥珠单抗共孵育后观察到RPS 6和RB磷酸化的显著上调。总之，蛋白质组学数据表明，EGFR在ERBB 2扩增的乳腺癌细胞中的高水平表达减弱了抗ERBB 2定向抗体的作用。总之，EGFR表达可作为诊断和预测生物标志物，以推进ERBB 2扩增乳腺癌患者的个性化治疗概念。
Increasing the efficacy of targeted cancer therapies requires the identification of robust biomarkers suitable for patient stratification. This study focused on the identification of molecular mechanisms causing resistance against the anti-ERBB2-directed therapeutic antibodies trastuzumab and pertuzumab presently used to treat patients with ERBB2-amplified breast cancer. Immunohistochemistry and clinical data were evaluated and yielded evidence for the existence of ERBB2-amplified breast cancer with high-level epidermal growth-factor receptor (EGFR) expression as a separate tumor entity. Because the proto-oncogene EGFR tightly interacts with ERBB2 on the protein level, the hypothesis that high-level EGFR expression might contribute to resistance against ERBB2-directed therapies was experimentally validated. SKBR3 and HCC1954 cells were chosen as model systems of EGFR-high/ERBB2-amplified breast cancer and exposed to trastuzumab, pertuzumab and erlotinib, respectively, and in combination. Drug impact was quantified in cell viability assays and on the proteomic level using reverse-phase protein arrays. Phosphoprotein dynamics revealed a significant downregulation of AKT signaling after exposure to trastuzumab, pertuzumab or a coapplication of both antibodies in SKBR3 cells but no concomitant impact on ERK1/2, RB or RPS6 phosphorylation. On the other hand, signaling was fully downregulated in SKBR3 cells after coinhibition of EGFR and ERBB2. Inhibitory effects in HCC1954 cells were driven by erlotinib alone, and a significant upregulation of RPS6 and RB phosphorylation was observed after coincubation with pertuzumab and trastuzumab. In summary, proteomic data suggest that high-level expression of EGFR in ERBB2-amplified breast cancer cells attenuates the effect of anti-ERBB2-directed antibodies. In conclusion, EGFR expression may serve as diagnostic and predictive biomarker to advance personalized treatment concepts of patients with ERBB2-amplified breast cancer.
登录
查看更多内容
影响因子：
50.3
作者：
Junttila, Teemu T.;Akita, Robert W.;Sliwkowski, Mark X.
通讯作者：
Sliwkowski, Mark X.
影响因子：
2.8
作者：
Chang, Shujian;Chen, Weichang;Yang, Jicheng
通讯作者：
Yang, Jicheng
影响因子：
14.9
作者：
Barrett T;Troup DB;Wilhite SE;Ledoux P;Evangelista C;Kim IF;Tomashevsky M;Marshall KA;Phillippy KH;Sherman PM;Muertter RN;Holko M;Ayanbule O;Yefanov A;Soboleva A
通讯作者：
Soboleva A
影响因子：
3.4
作者：
Loebke, Christian;Sueltmann, Holger;Korf, Ulrike
通讯作者：
Korf, Ulrike
DOI：
10.1073/pnas.89.10.4285
发表时间：
1992-05-15
影响因子：
11.1
作者：
CARTER, P;PRESTA, L;SHEPARD, HM
通讯作者：
SHEPARD, HM