National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland.
Population Health Sciences Division, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
Int J Oncol. 2017 Jun;50(6):2221-2228. doi: 10.3892/ijo.2017.3976. Epub 2017 Apr 26.
Although HER2 targeted therapies have improved prognosis for HER2 positive breast cancer, HER2 positive cancers which co-express ER have poorer response rates to standard HER2 targeted therapies, combined with chemotherapy, than HER2 positive/ER negative breast cancer. Administration of hormone therapy concurrently with chemotherapy and HER2 targeted therapy is generally not recommended. Using publically available gene expression datasets we found that high expression of IGF1R is associated with shorter disease-free survival in patients whose tumors are ER positive and HER2 positive. IGF1R is frequently expressed in HER2 positive breast cancer and there is significant evidence for crosstalk between IGF1R and both HER2 and ER. Therefore, we evaluated the therapeutic potential of targeting ER and IGF1R in cell line models of HER2/ER/IGF1R positive breast cancer, using tamoxifen and two IGF1R targeted tyrosine kinase inhibitors (NVP-AEW541 and BMS-536924). Dual inhibition of ER and IGF1R enhanced growth inhibition in the four HER2 positive cell lines tested and caused an increase in cell cycle arrest in G1 in BT474 cells. In addition, combined treatment with trastuzumab, tamoxifen and either of the IGF1R TKIs enhanced response compared to dual targeting strategies in three of the four HER2 positive breast cancer cell lines tested. Furthermore, in a cell line model of trastuzumab-resistant HER2 positive breast cancer (BT474/Tr), tamoxifen combined with an IGF1R TKI produced a similar enhanced response as observed in the parental BT474 cells suggesting that this combination may overcome acquired trastuzumab resistance in this model. Combining ER and IGF1R targeting with HER2 targeted therapies may be an alternative to HER2 targeted therapy and chemotherapy for patients with HER2/ER/IGF1R positive breast cancer.
虽然针对 HER2 的靶向治疗改善了 HER2 阳性乳腺癌的预后，但与 HER2 阳性/ER 阴性乳腺癌相比，同时表达 ER 的 HER2 阳性癌症对标准的 HER2 靶向治疗联合化疗的反应率较低。一般不建议同时给予激素治疗、化疗和 HER2 靶向治疗。我们利用公共基因表达数据集发现，在 ER 阳性和 HER2 阳性的患者中，IGF1R 高表达与无病生存期缩短相关。IGF1R 在 HER2 阳性乳腺癌中频繁表达，并且有大量证据表明 IGF1R 与 HER2 和 ER 之间存在串扰。因此，我们使用 HER2/ER/IGF1R 阳性乳腺癌的细胞系模型，评估了针对 ER 和 IGF1R 的治疗潜力，使用他莫昔芬和两种 IGF1R 靶向酪氨酸激酶抑制剂（NVP-AEW541 和 BMS-536924）。在四种测试的 HER2 阳性细胞系中，双重抑制 ER 和 IGF1R 增强了生长抑制作用，并导致 BT474 细胞中细胞周期停滞在 G1 期增加。此外，与双重靶向策略相比，曲妥珠单抗、他莫昔芬和两种 IGF1R TKIs 中的任何一种联合治疗都增强了三种测试的 HER2 阳性乳腺癌细胞系中的反应。此外，在曲妥珠单抗耐药的 HER2 阳性乳腺癌（BT474/Tr）的细胞系模型中，他莫昔芬联合 IGF1R TKI 产生了与在亲本 BT474 细胞中观察到的类似的增强反应，表明该组合可能在该模型中克服获得性曲妥珠单抗耐药。将 ER 和 IGF1R 靶向与 HER2 靶向治疗相结合，可能是 HER2/ER/IGF1R 阳性乳腺癌患者替代 HER2 靶向治疗和化疗的方法。
