Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095-7077, USA.
Mol Cancer Ther. 2010 Jun;9(6):1489-502. doi: 10.1158/1535-7163.MCT-09-1171. Epub 2010 May 25.
Trastuzumab and lapatinib provide clinical benefit to women with human epidermal growth factor receptor 2 (HER)-positive breast cancer. However, not all patients whose tumors contain the HER2 alteration respond. Consequently, there is an urgent need to identify new predictive factors for these agents. The aim of this study was to investigate the role of receptor tyrosine kinase signaling and phosphoinositide 3-kinase (PI3K)/AKT pathway activation in conferring resistance to trastuzumab and lapatinib. To address this question, we evaluated response to trastuzumab and lapatinib in a panel of 18 HER2-amplified cell lines, using both two- and three-dimensional culture. The SUM-225, HCC-1419, HCC-1954, UACC-893, HCC-1569, UACC-732, JIMT-1, and MDA-453 cell lines were found to be innately resistant to trastuzumab, whereas the MDA-361, MDA-453, HCC-1569, UACC-732, JIMT-1, HCC-202, and UACC-893 cells are innately lapatinib resistant. Lapatinib was active in de novo (SUM-225, HCC-1419, and HCC-1954) and in a BT-474 cell line with acquired resistance to trastuzumab. In these cells, trastuzumab had little effect on AKT phosphorylation, whereas lapatinib retained activity through the dephosphorylation of AKT. Increased phosphorylation of HER2, epidermal growth factor receptor, HER3, and insulin-like growth factor IR correlated with response to lapatinib but not trastuzumab. Loss of PTEN or the presence of activating mutations in PI3K marked resistance to trastuzumab, but lapatinib response was independent of these factors. Thus, increased activation of the PI3K/AKT pathway correlates with resistance to trastuzumab, which can be overcome by lapatinib. In conclusion, pharmacologic targeting of the PI3K/AKT pathway may provide benefit to HER2-positive breast cancer patients who are resistant to trastuzumab therapy.
曲妥珠单抗和拉帕替尼为人表皮生长因子受体 2（HER）阳性乳腺癌患者提供了临床获益。然而，并非所有肿瘤中含有 HER2 改变的患者都有反应。因此，迫切需要确定这些药物的新预测因子。本研究旨在探讨受体酪氨酸激酶信号转导和磷酸肌醇 3-激酶（PI3K）/AKT 通路激活在赋予曲妥珠单抗和拉帕替尼耐药中的作用。为了解决这个问题，我们使用二维和三维培养评估了 18 种 HER2 扩增细胞系中曲妥珠单抗和拉帕替尼的反应。SUM-225、HCC-1419、HCC-1954、UACC-893、HCC-1569、UACC-732、JIMT-1 和 MDA-453 细胞系对曲妥珠单抗固有耐药，而 MDA-361、MDA-453、HCC-1569、UACC-732、JIMT-1、HCC-202 和 UACC-893 细胞系对拉帕替尼固有耐药。拉帕替尼在新出现的（SUM-225、HCC-1419 和 HCC-1954）和曲妥珠单抗获得性耐药的 BT-474 细胞系中具有活性。在这些细胞中，曲妥珠单抗对 AKT 磷酸化几乎没有影响，而拉帕替尼通过 AKT 的去磷酸化保持活性。HER2、表皮生长因子受体、HER3 和胰岛素样生长因子 IR 的磷酸化增加与拉帕替尼的反应相关，但与曲妥珠单抗无关。PTEN 的缺失或 PI3K 中的激活突变标志着对曲妥珠单抗的耐药，但拉帕替尼的反应与这些因素无关。因此，PI3K/AKT 通路的过度激活与曲妥珠单抗耐药相关，而拉帕替尼可以克服这种耐药性。总之，PI3K/AKT 通路的药物靶向可能为曲妥珠单抗治疗耐药的 HER2 阳性乳腺癌患者带来益处。
