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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Direct and immune mediated antibody targeting of ERBB receptors in a colorectal cancer cell-line panel
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Direct and immune mediated antibody targeting of ERBB receptors in a colorectal cancer cell-line panel

机译：大肠癌细胞系中ERBB受体的直接和免疫介导的抗体靶向

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摘要

A significant proportion of colorectal cancer (CRC) patients are resistant to anti-ERBB1 [avian erythroblastic leukemia viral (v-erb-b) oncogene homolog, receptor for EGF] monoclonal antibodies (Mabs). We evaluated both immune and nonimmune effects of cetuximab (anti-ERBB1 Mab), trastuzumab (anti-ERBB2 Mab), pertuzumab (anti-ERBB2 Mab), and lapatinib (dual ERBB1 and ERBB2 tyrosine kinase inhibitor) in a large well-characterized panel of 64 CRC cell lines to find response predictive tumor characteristics. There was a significant correlation between the direct effects of cetuximab and lapatinib. Both agents were associated (P = 0.0004) with "triple' wild-type status in KRAS, BRAF, and PIK3CA exon 20. Most cell lines were resistant to the direct effects of anti-ERBB2 Mabs, suggesting that the effects of lapatinib might mainly be through ERBB1. Microarray mRNA expression profiles of sensitive and resistant cell lines showed that although ERBB1 receptor or ligand levels did not associate with cetuximab sensitivity, high levels of ERBB2 (P = 0.036) and amphiregulin (P = 0.026) predicted sensitivity to lapatinib. However, higher ERBB1 expression predicted susceptibility to cetuximab-induced antibody-dependent cellular cytotoxicity and occurred independently of KRAS/BRAF/ PIK3CA mutations (P = 0.69). Lapatinib may be an effective alternative therapy to cetuximab in triple wild-type tumors. Microarray analysis provides suggestive biomarkers for resistance. ERBB1 levels, independent of mutation status, predict immune killing. Therefore, anti-ERBB1 antibodies may be considered in CRC tumors with higher ERBB1 expression and favorable FcyR polymorphisms.
机译：很大一部分结直肠癌（CRC）患者对抗ERBB1 [禽红细胞白血病病毒（v-erb-b）癌基因同源物，是EGF的受体]单克隆抗体（Mabs）产生抗性。我们在一个特征明确的大型面板中评估了西妥昔单抗（抗ERBB1单抗），曲妥珠单抗（抗ERBB2单抗），帕妥珠单抗（抗ERBB2单抗）和拉帕替尼（双ERBB1和ERBB2酪氨酸激酶抑制剂）的免疫和非免疫作用64个CRC细胞系中寻找反应预测性肿瘤特征。西妥昔单抗和拉帕替尼的直接作用之间存在显着相关性。两种药物在KRAS，BRAF和PIK3CA外显子20中均具有“三联”野生型状态（P = 0.0004）。大多数细胞系对抗ERBB2 Mabs的直接作用有抗性，这表明拉帕替尼的作用可能主要是敏感和耐药细胞株的微阵列mRNA表达谱显示，尽管ERBB1受体或配体水平与西妥昔单抗敏感性无关，但高水平的ERBB2（P = 0.036）和双调蛋白（P = 0.026）预测对拉帕替尼敏感。然而，较高的ERBB1表达预示着对西妥昔单抗诱导的抗体依赖性细胞毒性的敏感性，并且独立于KRAS / BRAF / PIK3CA突变而发生（P = 0.69），拉帕替尼在三重野生型肿瘤中可能是西妥昔单抗的有效替代疗法。提供了提示性的抗药性生物标志物。ERBB1的水平与突变状态无关，可预测免疫杀伤力，因此，在结直肠癌中可考虑使用抗ERBB1抗体具有较高的ERBB1表达和良好的FcyR多态性的肿瘤。

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  • 作者

    Shazad Q. Ashraf; Angela M. Nicholls; Jennifer L. Wilding; Triantafyllia G. Ntouroupi; Neil J. Mortensen; Walter F. Bodmer;

  • 作者单位

    Cancer and Immunogenetics Laboratory, Department of Oncology, Weatherall Institute of Molecular Medicine, Oxford 0X3 9DS, United Kingdom,Department of Colorectal Surgery, Churchill Hospital, Headington, Oxford OX3 7U, United Kingdom,Nuffield Department of Surgical Sciences, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom;

    Cancer and Immunogenetics Laboratory, Department of Oncology, Weatherall Institute of Molecular Medicine, Oxford 0X3 9DS, United Kingdom;

    Cancer and Immunogenetics Laboratory, Department of Oncology, Weatherall Institute of Molecular Medicine, Oxford 0X3 9DS, United Kingdom;

    Cancer and Immunogenetics Laboratory, Department of Oncology, Weatherall Institute of Molecular Medicine, Oxford 0X3 9DS, United Kingdom;

    Department of Colorectal Surgery, Churchill Hospital, Headington, Oxford OX3 7U, United Kingdom,Nuffield Department of Surgical Sciences, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom;

    Cancer and Immunogenetics Laboratory, Department of Oncology, Weatherall Institute of Molecular Medicine, Oxford 0X3 9DS, United Kingdom;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    anti-ERBB1 therapy; immune-mediated killing; high throughput screening;

    机译：抗ERBB1疗法;免疫介导的杀伤高通量筛选;

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