Montaser Rugaia Z, Coley Helen M
Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK.
Cancers (Basel). 2018 Jun 20;10(6):209. doi: 10.3390/cancers10060209.
Although anti-endocrine therapies have significantly advanced the treatment of breast cancer, they pose the problem of acquired drug resistance. The oestrogen receptor (ER)-expressing breast cancer cell lines MCF-7 and T47D alongside their in vitro derived resistant counterparts MCF-7-TR (tamoxifen-resistant) and T47D-FR (fulvestrant-resistant) showed dual resistance to fulvestrant and tamoxifen in the presence of upregulated HER1 and HER2 growth factor receptors. Our study demonstrated that tamoxifen resistance and fulvestrant resistance are associated with collateral sensitivity to the tyrosine kinase inhibitors (TKIs) lapatinib ( < 0.0001) and afatinib ( < 0.0001). Further, we found that over time, the TKIs reactivated ERα protein and/or mRNA in tamoxifen- and fulvestrant-resistant cells. Combinations of anti-endocrine agents with afatinib gave rise to significantly enhanced levels of apoptosis in both T47D-FR and MCF-7-TR in a synergistic manner versus additive effects of agents used singly. This was associated with p27 induction for anti-endocrine-resistant cells versus parental cells. Our data supports the use of combination treatment utilising dual HER1/2 inhibitors in breast cancer patients showing resistance to multiple anti-endocrine agents.
尽管抗内分泌疗法显著推进了乳腺癌的治疗，但它们带来了获得性耐药问题。表达雌激素受体（ER）的乳腺癌细胞系MCF-7和T47D及其体外衍生的耐药对应物MCF-7-TR（对他莫昔芬耐药）和T47D-FR（对氟维司群耐药）在HER1和HER2生长因子受体上调的情况下，对氟维司群和他莫昔芬表现出双重耐药。我们的研究表明，他莫昔芬耐药和氟维司群耐药与对酪氨酸激酶抑制剂（TKIs）拉帕替尼（<0.0001）和阿法替尼（<0.0001）的 collateral 敏感性相关。此外，我们发现随着时间的推移，TKIs 在对他莫昔芬和氟维司群耐药的细胞中重新激活了 ERα 蛋白和/或 mRNA。抗内分泌药物与阿法替尼联合使用，与单独使用药物的相加作用相比，以协同方式显著增强了T47D-FR和MCF-7-TR中的细胞凋亡水平。这与抗内分泌耐药细胞相对于亲本细胞中p27的诱导有关。我们的数据支持在对多种抗内分泌药物耐药的乳腺癌患者中使用联合HER1/2抑制剂进行联合治疗。
