Department of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
Department of Biomedical Engineering, Knight Cancer Institute, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Quantitative Imaging Systems LLC, 1410 NW Kearney Street, #1114, Portland, OR 97209, USA.
Cell Syst. 2018 Mar 28;6(3):329-342.e6. doi: 10.1016/j.cels.2018.02.001. Epub 2018 Mar 14.
Extrinsic signals are implicated in breast cancer resistance to HER2-targeted tyrosine kinase inhibitors (TKIs). To examine how microenvironmental signals influence resistance, we monitored TKI-treated breast cancer cell lines grown on microenvironment microarrays composed of printed extracellular matrix proteins supplemented with soluble proteins. We tested ∼2,500 combinations of 56 soluble and 46 matrix microenvironmental proteins on basal-like HER2+ (HER2E) or luminal-like HER2+ (L-HER2+) cells treated with the TKIs lapatinib or neratinib. In HER2E cells, hepatocyte growth factor, a ligand for MET, induced resistance that could be reversed with crizotinib, an inhibitor of MET. In L-HER2+ cells, neuregulin1-β1 (NRG1β), a ligand for HER3, induced resistance that could be reversed with pertuzumab, an inhibitor of HER2-HER3 heterodimerization. The subtype-specific responses were also observed in 3D cultures and murine xenografts. These results, along with bioinformatic pathway analysis and siRNA knockdown experiments, suggest different mechanisms of resistance specific to each HER2+ subtype: MET signaling for HER2E and HER2-HER3 heterodimerization for L-HER2+ cells.
外在信号与乳腺癌对 HER2 靶向酪氨酸激酶抑制剂 (TKI) 的耐药性有关。为了研究微环境信号如何影响耐药性，我们监测了在由印刷细胞外基质蛋白和补充有可溶性蛋白的微环境微阵列上生长的 TKI 处理的乳腺癌细胞系。我们在接受 TKI 拉帕替尼或奈拉替尼治疗的基础样 HER2+（HER2E）或腔样 HER2+（L-HER2+）细胞上测试了约 2500 种 56 种可溶性和 46 种基质微环境蛋白的组合。在 HER2E 细胞中，肝细胞生长因子（MET 的配体）诱导了耐药性，而 MET 抑制剂克唑替尼可逆转这种耐药性。在 L-HER2+细胞中，神经调节蛋白 1-β1（NRG1β，HER3 的配体）诱导了耐药性，而 HER2-HER3 异二聚体抑制剂帕妥珠单抗可逆转这种耐药性。在 3D 培养物和鼠异种移植物中也观察到了这种亚型特异性反应。这些结果，以及生物信息通路分析和 siRNA 敲低实验，表明了每种 HER2+亚型特有的不同耐药机制：HER2E 为 MET 信号，L-HER2+为 HER2-HER3 异二聚体。
