Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: a role for altered tumor angiogenesis.
Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: a role for altered tumor angiogenesis.
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发表时间：
2001-07
期刊：
影响因子：
11.2
通讯作者：
A. Viloria‐Petit;T. Crombet;S. Jothy;D. Hicklin;P. Bőhlen;J. Schlaeppi;J. Rak;R. Kerbel
中科院分区：
文献类型：
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作者：
A. Viloria‐Petit;T. Crombet;S. Jothy;D. Hicklin;P. Bőhlen;J. Schlaeppi;J. Rak;R. Kerbel
表皮生长因子受体（EGFR）信号传导抑制剂是临床上显示出巨大前景的癌症治疗新药之一。然而，由于肿瘤细胞遗传不稳定性而对这些药物产生获得性耐药性的可能性尚未被探索。在这里，我们报告的实验推导和特性的细胞变异获得复发性肿瘤异种移植的人A431鳞状细胞癌，经过两个连续的治疗周期与三种不同的抗EGFR单克隆抗体之一：mR3，hR3，或C225。对2周治疗期的初始响应通常是完全肿瘤消退，并且在三个抗体组之间没有显著差异。然而，肿瘤经常在接种部位重新出现，通常在延长的潜伏期后，并且大多数肿瘤对第二轮治疗变得难治。从这种耐药肿瘤建立的细胞系保留了高EGFR表达，对抗EGFR抗体或配体的正常敏感性，并且当与体外亲本系相比时生长速率不变。相比之下，A431细胞变体相对于亲本系在体内表现出加速的生长速率和显著减弱的对抗EGFR抗体的应答。由于报道了EGFR抑制剂对血管内皮生长因子（VEGF）表达的抑制作用，以及VEGF在A431肿瘤异种移植物的血管生成和生长中的作用，因此检查了相对VEGF表达。6个耐药变异体中有5个表达VEGF水平增加，这表明体外血管生成潜力和体内肿瘤血管生成增加。此外，通过基因转染获得的A431细胞变体中VEGF表达的升高使得细胞在体内对抗EGFR抗体具有显著抗性。综上所述，结果表明，至少在A431系统中，表现出获得性抗EGFR抗体抗性的变体可以在体内出现，并且可以至少部分地通过涉及选择具有增加的血管生成潜力的肿瘤细胞亚群的机制来实现。
Inhibitors of epidermal growth factor receptor (EGFR) signaling are among the novel drugs showing great promise for cancer treatment in the clinic. However, the possibility of acquired resistance to such drugs because of tumor cell genetic instabilities has not yet been explored. Here we report the experimental derivation and properties of such cell variants obtained from recurrent tumor xenografts of the human A431 squamous cell carcinoma, after two consecutive cycles of therapy with one of three different anti-EGFR monoclonal antibodies: mR3, hR3, or C225. Initial response to a 2-week period of treatment was generally total tumor regression and was not significantly different among the three antibody groups. However, tumors often reappeared at the site of inoculation, generally after prolonged latency periods, and most of the tumors became refractory to a second round of therapy. Cell lines established from such resistant tumors retained high EGFR expression, normal sensitivity to anti-EGFR antibody or ligand, and unaltered growth rate when compared with the parental line in vitro. In contrast, the A431 cell variants exhibited an accelerated growth rate and a significantly attenuated response to anti-EGFR antibodies in vivo relative to the parental line. Because of the reported suppressive effect of EGFR inhibitors on vascular endothelial growth factor (VEGF) expression, and the demonstrated role of VEGF in the angiogenesis and growth of A431 tumor xenografts, relative VEGF expression was examined. Five of six resistant variants expressed increased levels of VEGF, which paralleled an increase in both angiogenic potential in vitro and tumor angiogenesis in vivo. In addition, elevated expression of VEGF in variants of A431 cells obtained by gene transfection rendered the cells significantly resistant to anti-EGFR antibodies in vivo. Taken together, the results suggest that, at least in the A431 system, variants displaying acquired resistance to anti-EGFR antibodies can emerge in vivo and can do so, at least in part, by mechanisms involving the selection of tumor cell subpopulations with increased angiogenic potential.