Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Paris, France.
Institut National de la Santé et de la Recherche Médicale (INSERM) U938, Paris, France.
Clin Cancer Res. 2018 Jun 1;24(11):2548-2558. doi: 10.1158/1078-0432.CCR-17-3187. Epub 2018 Feb 28.
There is extensive cross-talk between VEGF- and EGFR-pathway signaling in colorectal cancer. However, combinations of VEGF- and EGFR-targeted monoclonal antibodies (mAb) show disappointing activity, in particular for patients with mutant Previous results show that tyrosine kinase inhibitors (TKI) can be active in colorectal cancer models resistant to mAbs. This prompted us to examine whether the activity of bevacizumab can be increased by combination with erlotinib. The antitumor activity of bevacizumab, erlotinib, and their combination was determined in colorectal cancer models with different status and bevacizumab sensitivity. EGFR/VEGF pathway activation was characterized by immunohistochemistry, Western blot, and ELISA assays. The influence of cetuximab and erlotinib on EGF-mediated migration and the EGFR-EGF ligand feedback loop was established in colorectal cancer cell lines with different status. The addition of erlotinib increased bevacizumab activity in all models independent of status. Bevacizumab exposure was accompanied by marked EGFR activation in tumor cells as well as in tumor-associated endothelial cells (TECs) and resulted in strong accumulation of intracellular EGFR, which could be attenuated by erlotinib. In cellular models, erlotinib was able to attenuate EGF-mediated functions in all cell lines independent of status while cetuximab only showed activity in wild-type cells. These results should provide a molecular framework to better understand the increased activity of the bevacizumab-erlotinib combination, compared with bevacizumab alone, in the GERCOR DREAM phase III clinical trial. Differential activity of mAbs and TKIs targeting the same signaling pathway is likely applicable for other tumor types. .
血管内皮生长因子（VEGF）和表皮生长因子受体（EGFR）通路信号之间存在广泛的串扰，在结直肠癌中也是如此。然而，VEGF 和 EGFR 靶向单克隆抗体（mAb）的联合应用效果并不理想，特别是对于突变型患者。之前的结果表明，酪氨酸激酶抑制剂（TKI）在 mAb 耐药的结直肠癌模型中可能具有活性。这促使我们研究贝伐珠单抗与厄洛替尼联合应用是否能增加其活性。我们在不同 EGFR 状态和贝伐珠单抗敏感性的结直肠癌模型中，检测了贝伐珠单抗、厄洛替尼及其联合用药的抗肿瘤活性。通过免疫组化、Western blot 和 ELISA 检测，分析 EGFR/VEGF 通路的激活情况。在具有不同 EGFR 状态的结直肠癌细胞系中，建立了西妥昔单抗和厄洛替尼对 EGF 介导的迁移和 EGFR-EGF 配体反馈环的影响。厄洛替尼的加入增加了所有模型中贝伐珠单抗的活性，而与 EGFR 状态无关。贝伐珠单抗的暴露伴随着肿瘤细胞以及肿瘤相关内皮细胞（TEC）中 EGFR 的明显激活，并导致细胞内 EGFR 的强烈积累，厄洛替尼可减弱这种积累。在细胞模型中，厄洛替尼能够减弱所有细胞系中 EGF 介导的功能，而与 EGFR 状态无关，而西妥昔单抗仅在 EGFR 野生型细胞中具有活性。这些结果为更好地理解贝伐珠单抗-厄洛替尼联合应用相对于单独使用贝伐珠单抗在 GERCOR DREAM 三期临床试验中的活性增强提供了分子框架。针对同一信号通路的 mAb 和 TKI 的不同活性可能适用于其他肿瘤类型。
