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Cell Syst. 2018 Mar 28;6(3):329-342.e6. doi: 10.1016/j.cels.2018.02.001. Epub 2018 Mar 14.

Microenvironment-Mediated Mechanisms of Resistance to HER2 Inhibitors Differ between HER2+ Breast Cancer Subtypes.

Author information

1
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.
2
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.
3
Department of Radiology, Brigham & Women's Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115, USA.
4
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
5
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. Electronic address: grayjo@ohsu.edu.
6
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. Electronic address: korkola@ohsu.edu.

Abstract

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.

KEYWORDS:

HER2+ breast cancer subtypes; HER3; HGF; NRG1β; crizotinib; drug resistance; lapatinib; microenvironment; neratinib; pertuzumab

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