Chakraborty Ashok K, Liang Ke, DiGiovanna Michael P
Department of Internal Medicine, Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510, USA.
Cancer Res. 2008 Mar 1;68(5):1538-45. doi: 10.1158/0008-5472.CAN-07-5935.
The insulin-like growth factor I receptor (IGFIR) and HER2 display important signaling interactions in breast cancer. We examined the effect of combinations of antagonists of these receptors using two human breast cancer cell lines: BT474 (HER2+, IGFIR low) and MCF7 (HER2 low, IGFIR high). In BT474 cells, growth was inhibited by HER2 antagonists but not by IGFIR antagonists; however, IGFIR antagonists enhanced the effect of HER2 inhibitors. In MCF7 cells, growth was inhibited by IGFIR antagonists but not by HER2 antagonists; however, HER2 antagonism enhanced the effect of IGFIR inhibitors. Synergistic inhibition of soft agar growth was also observed. Although HER2 and IGFIR antagonists individually only minimally affected cell cycle, their combination gave a small enhancement of their effects. No single receptor-targeting drug was capable of inducing apoptosis, but combining antagonists of both receptors induced a dramatic degree of apoptosis in both cell lines. Induction of apoptosis was most striking in MCF7 cells using a Herceptin/IGFIR antagonist combination despite these cells being HER2 nonoverexpressing. Toward understanding the mechanism of these effects, we detected coassociation IGFIR and HER2 in both cell lines. Specific inhibitors of one of these receptors could cross-inhibit the activity of the other. Targeting both receptors gave the maximal inhibition of their downstream extracellular signal-regulated kinase 1/2 and AKT signaling pathways. Hence, such drug combinations may be clinically useful and may be beneficial even in tumors in which single drugs are inactive, as exemplified by the effect of the HER2/IGFIR inhibitor combination in HER2 nonoverexpressing MCF7 cells.
胰岛素样生长因子I受体（IGFIR）和HER2在乳腺癌中显示出重要的信号相互作用。我们使用两种人乳腺癌细胞系：BT474（HER2阳性，IGFIR低表达）和MCF7（HER2低表达，IGFIR高表达），研究了这些受体拮抗剂联合使用的效果。在BT474细胞中，HER2拮抗剂可抑制细胞生长，而IGFIR拮抗剂则无此作用；然而，IGFIR拮抗剂可增强HER2抑制剂的效果。在MCF7细胞中，IGFIR拮抗剂可抑制细胞生长，而HER2拮抗剂则无此作用；然而，HER2拮抗剂可增强IGFIR抑制剂的效果。在软琼脂生长实验中也观察到了协同抑制作用。虽然HER2和IGFIR拮抗剂单独使用时对细胞周期的影响很小，但它们联合使用时可使效果略有增强。没有一种单一的靶向受体药物能够诱导细胞凋亡，但联合使用两种受体的拮抗剂可在两种细胞系中诱导显著程度的细胞凋亡。尽管MCF7细胞不高表达HER2，但使用赫赛汀/IGFIR拮抗剂联合用药时，诱导细胞凋亡的效果最为显著。为了了解这些作用的机制，我们在两种细胞系中均检测到了IGFIR和HER2的共结合。其中一种受体的特异性抑制剂可交叉抑制另一种受体的活性。同时靶向两种受体可最大程度地抑制其下游的细胞外信号调节激酶1/2和AKT信号通路。因此，这种药物联合使用可能具有临床应用价值，即使在单一药物无效的肿瘤中也可能有益，如HER2/IGFIR抑制剂联合用药对不高表达HER2的MCF7细胞的作用所示。
