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

Spencer S. Watson, Mark Dane, Koei Chin, Zuzana Tatarova, Moqing Liu, Tiera Liby, Wallace Thompson, Rebecca Smith, Michel Nederlof, Elmar Bucher, David Kilburn, Matthew Whitman, Damir Sudar, Gordon B. Mills, Laura M. Heiser, Oliver Jonas, Joe Gray, James Korkola

Research output: Contribution to journalArticlepeer-review

49 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)329-342.e6
JournalCell Systems
Issue number3
StatePublished - Mar 28 2018


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

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology
  • Cell Biology


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