Department of Oncology, Chaoyang Central Hospital, Chaoyang, Liaoning Province, China.
Department of Gastric Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China.
Mol Carcinog. 2018 Aug;57(8):1008-1016. doi: 10.1002/mc.22821. Epub 2018 Apr 24.
Gefitinib exhibits very limited efficacy in gastric cancer (GC). Indeed, the limited clinical results obtained with gefitinib alone justify investigation of additional therapeutic strategies. Here, we demonstrate the importance of EGFR and HER2 in GC malignancy using RNA interference (RNAi). Additionally, we explored the ability of RNAi targeting EGFR and HER2 to enhance the sensitivity of GC cells to gefitinib. Specific small interfering RNAs (siRNAs) significantly inhibited mRNA and protein expression of target genes. EGFR-specific siRNA, EGFR/HER2 siRNAs, and gefitinib inhibited growth and induced apoptosis in GC cell lines in a dose-dependent manner. In contrast, resistance to HER2-siRNA-induced growth inhibition and apoptosis was linked to compensatory activation of EGFR. Moreover, gefitinib dramatically reduced p-EGFR and p-HER2 levels in the cell lines tested, and sensitivity to gefitinib was enhanced through dual silencing of EGFR and HER2 via suppression of AKT and ERK activation. These findings are in agreement with the profound inhibitory effect of gefitinib on activation of both EGFR and HER2. Overall, EGFR/HER2 knockdown by siRNAs further decreased the growth of GC cells treated with gefitinib alone, confirming that single-agent drug targeting does not achieve a maximal biological effect. The combination of gefitinib with EGFR/HER2 siRNAs should be further investigated as a new strategy for the treatment of GC and other EGFR/HER2-dependent cancers.
吉非替尼在胃癌（GC）中的疗效非常有限。事实上，吉非替尼单独应用的有限临床结果证明需要探索其他治疗策略。在这里，我们使用 RNA 干扰（RNAi）来证明 EGFR 和 HER2 在 GC 恶性肿瘤中的重要性。此外，我们还探讨了针对 EGFR 和 HER2 的 RNAi 靶向增强 GC 细胞对吉非替尼敏感性的能力。特异性小干扰 RNA（siRNA）显著抑制了靶基因的 mRNA 和蛋白表达。EGFR 特异性 siRNA、EGFR/HER2 siRNA 和吉非替尼以剂量依赖性方式抑制 GC 细胞系的生长并诱导细胞凋亡。相比之下，HER2-siRNA 诱导的生长抑制和凋亡的抗性与 EGFR 的代偿性激活有关。此外，吉非替尼显著降低了所测试细胞系中 p-EGFR 和 p-HER2 的水平，并且通过抑制 AKT 和 ERK 激活来双重沉默 EGFR 和 HER2 可增强对吉非替尼的敏感性。这些发现与吉非替尼对 EGFR 和 HER2 激活的深刻抑制作用一致。总的来说，siRNA 下调 EGFR/HER2 进一步降低了单独用吉非替尼治疗的 GC 细胞的生长，证实了单一药物靶向并不能达到最大的生物学效应。吉非替尼与 EGFR/HER2 siRNA 的联合应用应作为治疗 GC 和其他 EGFR/HER2 依赖性癌症的新策略进一步研究。
