Synergistic effects of various Her inhibitors in combination with IGF-1R, C-MET and Src targeting agents in breast cancer cell lines.
Synergistic effects of various Her inhibitors in combination with IGF-1R, C-MET and Src targeting agents in breast cancer cell lines.
复制标题
DOI：
10.1038/s41598-017-04301-8
复制
发表时间：
2017-06-21
影响因子：
4.6
通讯作者：
Modjtahedi H
中科院分区：
文献类型：
--
作者：
Stanley A;Ashrafi GH;Seddon AM;Modjtahedi H
据报道，约25%的人类乳腺癌中存在HER 2过表达。尽管最近在HER 2靶向治疗方面取得了进展，但许多患者仍然对此类治疗产生原发性和继发性耐药，其机制尚不清楚。在这里，我们研究了一组乳腺癌细胞系对单独使用各种类型的HER家族抑制剂或与其他酪氨酸激酶抑制剂或化疗药物联合治疗的敏感性。我们发现，第二代不可逆HER家族抑制剂（尤其是阿法替尼和来那替尼）治疗在抑制乳腺癌细胞生长、迁移和下游细胞信号传导方面比第一代可逆抑制剂治疗更有效。在该组中的三种HER 2过表达细胞系中，SKBr 3和BT474对HER家族抑制剂治疗高度敏感，而MDA-MB-453相对耐药。HER家族抑制剂与NVP-AEW 541、达沙替尼或克唑替尼（分别为IGF-1 R、Src和c-Met/ALK的抑制剂）联合使用，在一些检查的细胞系中产生协同效应。特别地，用Src和HER家族成员抑制剂的组合治疗导致MDA-MB 453细胞的协同生长抑制，暗示Src作为对HER 2靶向剂的抗性的介体。我们的研究结果表明，HER家族抑制剂与其他TKI（如达沙替尼）联合使用可能在某些乳腺癌亚型中具有治疗优势，值得进一步研究。
Overexpression of HER2 has been reported in around 25% of human breast cancers. Despite recent advances in HER2 targeted therapy, many patients still experience primary and secondary resistance to such treatments, the mechanisms for which are poorly understood. Here, we investigated the sensitivity of a panel of breast cancer cell lines to treatment with various types of HER-family inhibitors alone or in combination with other tyrosine kinase inhibitors or chemotherapeutic agents. We found that treatment with the second-generation irreversible HER-family inhibitors, particularly afatinib and neratinib, were more effective than treatment with the first-generation reversible inhibitors in inhibiting growth, migration and downstream cell signalling in breast cancer cells. Of the three HER2 overexpressing cell lines in this panel, SKBr3 and BT474 were highly sensitive to treatment with HER-family inhibitors, while MDA-MB-453 was comparatively resistant. Combinations of HER-family inhibitors with NVP-AEW541, dasatinib or crizotinib (inhibitors of IGF-1R, Src and c-Met/ALK, respectively) led to synergistic effects in some of the cell lines examined. In particular, treatment with a combination of Src and HER-family member inhibitors resulted in synergistic growth inhibition of MDA-MB453 cells, implicating Src as a mediator of resistance to HER2-targeting agents. Our results suggest that combining HER-family inhibitors with other TKIs such as dasatinib may have therapeutic advantages in certain breast cancer subtypes and warrants further investigation.