@article{4445fee3868c4e089a101b85004d94c9,
title = "Microenvironment-Mediated Mechanisms of Resistance to HER2 Inhibitors Differ between HER2+ Breast Cancer Subtypes",
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. We describe a powerful platform for discovery of microenvironment signals that influence drug responses. We show through application of the platform to HER2+ breast cancer cell lines that NRG1β and HGF suppress responses to lapatinib and neratinib in L-HER2+ and HER2E cells, respectively. We show that these differences are caused by differences in epigenomic status and regulatory pathway use between L-HER2+ and HER2E breast cancers. We also present evidence suggesting that microenvironment-mediated resistance to HER2-targeted tyrosine kinase inhibitors can be overcome in L-HER2+ cancers by co-treatment with pertuzumab, and in HER2E cancers by co-treatment with crizotinib or trametinib.",
keywords = "HER2+ breast cancer subtypes, HER3, HGF, NRG1β, crizotinib, drug resistance, lapatinib, microenvironment, neratinib, pertuzumab",
author = "Watson, {Spencer S.} and Mark Dane and Koei Chin and Zuzana Tatarova and Moqing Liu and Tiera Liby and Wallace Thompson and Rebecca Smith and Michel Nederlof and Elmar Bucher and David Kilburn and Matthew Whitman and Damir Sudar and Mills, {Gordon B.} and Heiser, {Laura M.} and Oliver Jonas and Joe Gray and James Korkola",
note = "Funding Information: Research reported in this publication was supported by the NIH Common Fund Library of Network Cellular Signatures (LINCS) grant HG008100 (J.W.G., G.B.M., L.M.H., and J.E.K.) and the Susan G. Komen Foundation award SAC110012 (J.W.G.). S.S.W. was supported by the National Cancer Institute of the NIH under award number F31CA200322 . Additional support was provided by the Knight Cancer Institute NCI grant 5P30CA069533-16 (J.W.G.), NIH grant CA195469 (J.W.G), and the Prospect Creek Foundation (J.W.G. and J.E.K.). O.J. was supported by the Brigham Research Institute , Director{\textquoteright}s Transformative Award. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health nor does it reflect the position or the policy of the Government, and no official endorsement should be inferred. Mass spectrometric analysis was performed by the OHSU Proteomics Shared Resource with partial support from NIH core grants P30EY010572 and P30CA069533 , and shared instrument grant S10OD012246 . Microscopy and image cytometry was supported by the Knight Cancer Institute Multiscale Microscopy Core with partial support from the OHSU Center for Spatial Systems Biomedicine (OCSSB), and the MJ Murdock Charitable Trust . RPPA data were generated at the RPPA Core facility at the MD Anderson Cancer Center supported by NCI grant CA16672 . We would like to thank Dr. Mark LaBarge (malabarge@lbl.gov) at Lawrence Berkeley National Labs (now at City of Hope) for his contributions to the development of the MEMA platform. In addition, we would like to thank Johann Gagnon-Bartsch for his work on array data normalization and the RUV pipeline. We would also like to thank Dr. Wassana Yantasee, Shenda Gu, and Taylor Ishida for their generous assistance with the murine xenograft project, and Ting Zheng for her assistance with proximity ligation assays. Funding Information: Research reported in this publication was supported by the NIH Common Fund Library of Network Cellular Signatures (LINCS) grant HG008100 (J.W.G., G.B.M., L.M.H., and J.E.K.) and the Susan G. Komen Foundation award SAC110012 (J.W.G.). S.S.W. was supported by the National Cancer Institute of the NIH under award number F31CA200322. Additional support was provided by the Knight Cancer Institute NCI grant 5P30CA069533-16 (J.W.G.), NIH grant CA195469 (J.W.G), and the Prospect Creek Foundation (J.W.G. and J.E.K.). O.J. was supported by the Brigham Research Institute, Director's Transformative Award. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health nor does it reflect the position or the policy of the Government, and no official endorsement should be inferred. Mass spectrometric analysis was performed by the OHSU Proteomics Shared Resource with partial support from NIH core grants P30EY010572 and P30CA069533, and shared instrument grant S10OD012246. Microscopy and image cytometry was supported by the Knight Cancer Institute Multiscale Microscopy Core with partial support from the OHSU Center for Spatial Systems Biomedicine (OCSSB), and the MJ Murdock Charitable Trust. RPPA data were generated at the RPPA Core facility at the MD Anderson Cancer Center supported by NCI grant CA16672. We would like to thank Dr. Mark LaBarge (malabarge@lbl.gov) at Lawrence Berkeley National Labs (now at City of Hope) for his contributions to the development of the MEMA platform. In addition, we would like to thank Johann Gagnon-Bartsch for his work on array data normalization and the RUV pipeline. We would also like to thank Dr. Wassana Yantasee, Shenda Gu, and Taylor Ishida for their generous assistance with the murine xenograft project, and Ting Zheng for her assistance with proximity ligation assays. Publisher Copyright: {\textcopyright} 2018 The Authors",
year = "2018",
month = mar,
day = "28",
doi = "10.1016/j.cels.2018.02.001",
language = "English (US)",
volume = "6",
pages = "329--342.e6",
journal = "Cell Systems",
issn = "2405-4712",
publisher = "Cell Press",
number = "3",
}