Abstract LB-217: Microenvironment mediated mechanisms of resistance to HER2 inhibitors differ between HER2+ breast cancer subtypes

Clinical responses of HER2+ breast cancers to tyrosine kinase inhibitors (TKIs) are often limited by de novo and acquired resistance. Recent studies have shown that the tumor microenvironment has a substantial capacity to generate signals and create niches that enable otherwise sensitive cells to avoid therapeutic control. We describe here the use of MicroEnvironment MicroArrays (MEMAs) to identify specific signals from the tumor microenvironment that reduce sensitivity to small molecule HER2 targeted TKIs. We show here that responses to these signals differ between HER2+ cells that express transcriptional signatures associated with basal (HER2E) or luminal (L-HER2+) HER2+ subtypes. Specifically, we show that HER2E cell lines are rescued from the TKIs lapatinib and neratinib by hepatocyte growth factor (HGF), while L-HER2+ cell lines are rescued by neuregulin1-β1 (NRG1β). We further show that these divergent responses are due to differential use of the PI3K and MAPK pathways, and expression of receptors HER3 and MET. This is supported by transcriptomics of human tumors performed by The Cancer Genome Atlas. HGF and NRG1β are expressed in the stroma of primary mammary tumors, but can also be highly expressed in common sites of both HER2E and L-HER2+ metastasis. We show that NRG1β mediated resistance in L-HER2+ lines is reversed by inhibiting HER2-HER3 dimers with pertuzumab, while HGF mediated resistance in HER2E lines is reversed with the MET inhibitor crizotinib. These studies suggest that L-HER2+ and HER2E tumors should be treated as separate diseases and that treatments should be tailored to counter microenvironment mediated resistance mechanisms that may differ between metastatic locations based on local production and action of growth factors. Citation Format: Spencer Watson, Joe Gray, James Korkola, Mark Dane, Laura Hesier, Koei Chin, Gordon Mills. Microenvironment mediated mechanisms of resistance to HER2 inhibitors differ between HER2+ breast cancer subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-217. doi:10.1158/1538-7445.AM2017-LB-217