Cancer Research Laboratory, University Hospital Research Center (CPE-HCPA), Federal University of Rio Grande do Sul, 90035-003 Porto Alegre, RS, Brazil.
Biochem Biophys Res Commun. 2012 Aug 24;425(2):328-32. doi: 10.1016/j.bbrc.2012.07.091. Epub 2012 Jul 25.
The clinical success of targeted treatment of colorectal cancer (CRC) is often limited by resistance to anti-epidermal growth factor receptor (EGFR) therapy. The neurotrophin brain-derived neurotrophic factor (BDNF) and its receptor TrkB have recently emerged as anticancer targets, and we have previously shown increased BDNF levels in CRC tumor samples. Here we report the findings from in vitro experiments suggesting that BDNF/TrkB signaling can protect CRC cells from the antitumor effects of EGFR blockade. The anti-EGFR monoclonal antibody cetuximab reduced both cell proliferation and the mRNA expression of BDNF and TrkB in human HT-29 CRC cells. The inhibitory effect of cetuximab on cell proliferation and survival was counteracted by the addition of human recombinant BDNF. Finally, the Trk inhibitor K252a synergistically enhanced the effect of cetuximab on cell proliferation, and this effect was blocked by BDNF. These results provide the first evidence that increased BDNF/TrkB signaling might play a role in resistance to EGFR blockade. Moreover, it is possible that targeting TrkB could potentiate the anticancer effects of anti-EGFR therapy.
针对结直肠癌（CRC）的靶向治疗的临床疗效常常受到抗表皮生长因子受体（EGFR）治疗的耐药性限制。神经营养因子脑源性神经营养因子（BDNF）及其受体 TrkB 最近已成为抗癌靶点，我们之前已经显示 CRC 肿瘤样本中的 BDNF 水平升高。在这里，我们报告了体外实验的结果，表明 BDNF/TrkB 信号可以保护 CRC 细胞免受 EGFR 阻断的抗肿瘤作用。抗 EGFR 单克隆抗体西妥昔单抗降低了人 HT-29 CRC 细胞的细胞增殖和 BDNF 和 TrkB 的 mRNA 表达。人重组 BDNF 的添加抵消了西妥昔单抗对细胞增殖和存活的抑制作用。最后，Trk 抑制剂 K252a 协同增强了西妥昔单抗对细胞增殖的作用，而这种作用被 BDNF 阻断。这些结果首次提供了证据表明，增加的 BDNF/TrkB 信号可能在 EGFR 阻断的耐药性中起作用。此外，靶向 TrkB 有可能增强抗 EGFR 治疗的抗癌作用。
