Viloria-Petit A, Crombet T, Jothy S, Hicklin D, Bohlen P, Schlaeppi J M, Rak J, Kerbel R S
Molecular and Cellular Biology Research, Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada.
Cancer Res. 2001 Jul 1;61(13):5090-101.
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.
表皮生长因子受体（EGFR）信号通路抑制剂是一类在临床癌症治疗中显示出巨大潜力的新型药物。然而，由于肿瘤细胞基因不稳定而导致对这类药物产生获得性耐药的可能性尚未得到研究。在此，我们报告了从人A431鳞状细胞癌的复发性肿瘤异种移植瘤中获得的此类细胞变体的实验衍生过程及其特性，该肿瘤经过三个不同的抗EGFR单克隆抗体（mR3、hR3或C225）之一的两个连续治疗周期。对为期2周的治疗的初始反应通常是肿瘤完全消退，且三个抗体组之间无显著差异。然而，肿瘤通常在接种部位重新出现，一般在较长的潜伏期后，并且大多数肿瘤对第二轮治疗变得难治。从这类耐药肿瘤建立的细胞系与亲代细胞系相比，在体外保留了高EGFR表达、对抗EGFR抗体或配体的正常敏感性以及未改变的生长速率。相反，A431细胞变体在体内相对于亲代细胞系表现出加速的生长速率和对抗EGFR抗体的显著减弱的反应。由于已有报道称EGFR抑制剂对血管内皮生长因子（VEGF）表达有抑制作用，且VEGF在A431肿瘤异种移植瘤的血管生成和生长中发挥作用，因此检测了相对VEGF表达。六个耐药变体中有五个表达的VEGF水平升高，这与体外血管生成潜力和体内肿瘤血管生成的增加平行。此外，通过基因转染获得的A431细胞变体中VEGF表达的升高使细胞在体内对抗EGFR抗体具有显著抗性。综上所述，结果表明，至少在A431系统中，显示出对抗EGFR抗体获得性耐药的变体可在体内出现，并且至少部分是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实现的。
Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai). 2002-3
Front Pharmacol. 2024-4-22
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