Authors' Affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
Mol Cancer Ther. 2014 May;13(5):1345-55. doi: 10.1158/1535-7163.MCT-13-1033. Epub 2014 Mar 14.
EGFR blocking antibodies are approved for the treatment of colorectal cancer and head and neck squamous cell carcinoma (HNSCC). Although ERBB3 signaling has been proposed to limit the effectiveness of EGFR inhibitors, the underlying molecular mechanisms are not fully understood. To gain insight into these mechanisms, we generated potent blocking antibodies against ERBB3 (REGN1400) and EGFR (REGN955). We show that EGFR and ERBB3 are coactivated in multiple HNSCC cell lines and that combined blockade of EGFR and ERBB3 inhibits growth of these cell lines more effectively than blockade of either receptor alone. Blockade of EGFR with REGN955 strongly inhibited activation of ERK in HNSCC cell lines, whereas blockade of ERBB3 with REGN1400 strongly inhibited activation of Akt; only the combination of the 2 antibodies blocked both of these essential downstream pathways. We used a HER2 blocking antibody to show that ERBB3 phosphorylation in HNSCC and colorectal cancer cells is strictly dependent on association with HER2, but not EGFR, and that neuregulin 1 activates ERBB3/HER2 signaling to reverse the effect of EGFR blockade on colorectal cancer cell growth. Finally, although REGN1400 and REGN955 as single agents slowed the growth of HNSCC and colorectal cancer xenografts, the combination of REGN1400 plus REGN955 caused significant tumor regression. Our results indicate that activation of the Akt survival pathway by ERBB3/HER2 limits the effectiveness of EGFR inhibition, suggesting that REGN1400, which is currently in a phase I clinical trial, could provide benefit when combined with EGFR blocking antibodies.
表皮生长因子受体（EGFR）阻断抗体已被批准用于治疗结直肠癌和头颈部鳞状细胞癌（HNSCC）。尽管 ERBB3 信号已被提出限制 EGFR 抑制剂的效果，但潜在的分子机制尚不完全清楚。为了深入了解这些机制，我们生成了针对 ERBB3（REGN1400）和 EGFR（REGN955）的有效阻断抗体。我们表明，多种 HNSCC 细胞系中存在 EGFR 和 ERBB3 的共激活，并且 EGFR 和 ERBB3 的联合阻断比单独阻断任一受体更有效地抑制这些细胞系的生长。REGN955 阻断 EGFR 强烈抑制 HNSCC 细胞系中 ERK 的激活，而 REGN1400 阻断 ERBB3 强烈抑制 Akt 的激活；只有这两种抗体的组合才能阻断这两条必不可少的下游途径。我们使用 HER2 阻断抗体表明，HNSCC 和结直肠癌细胞中的 ERBB3 磷酸化严格依赖于与 HER2 的结合，而不是 EGFR，并且神经调节蛋白 1 激活 ERBB3/HER2 信号以逆转 EGFR 阻断对结直肠癌细胞生长的影响。最后，尽管 REGN1400 和 REGN955 作为单一药物可减缓 HNSCC 和结直肠癌异种移植物的生长，但 REGN1400 加 REGN955 的组合导致了显著的肿瘤消退。我们的结果表明，ERBB3/HER2 激活 Akt 存活途径限制了 EGFR 抑制的效果，这表明目前正在进行 I 期临床试验的 REGN1400 与 EGFR 阻断抗体联合使用可能会带来益处。
