86P The Role of Adam17 in Her2 Moderately Expressing Breast Cancer

Abstract

ABSTRACT Trastuzumab has been shown to increase the survival of HER2 positive breast cancer (HER2 3+) patients and some clinical trials revealed that patients with moderately expressed HER2 (HER2 2+) breast cancer may also respond. However, there is a need to further understand the mechanisms of resistance to trastuzumab and to explore other targeted therapies. Members of a disintegrin and metalloproteases (ADAMs) are responsible for shedding of a variety of ErbB ligands. The most important members are ADAM10 and ADAM17 and we investigated the role of these ADAMs in trastuzumab treatment and resistance in HER2 2+ breast cancer cell lines. We first assessed the effect of trastuzumab on MDA-MB-453 and MDA-MB-361 cells and confirmed that those are less sensitive than HER2 positive SKBR3 cells but respond better than MCF7 cells. We found that trastuzumab treatment does not decrease pHER2 in HER2 2+ expressing cells. We previously showed that ADAM17 mediated heregulin release maintains HER2 phosphorylation in HER2 3+ breast cancer cells. Therefore we proceeded to investigate the levels of ADAM17 and heregulin and found an increase of both in HER2 2+ cells in comparison to SKBR3 cells. Interestingly, the use of a specific anti ADAM17 antibody leads to a decrease of pPKB as well as pHER3 and pHER2 in MDA-MB-453 cells. Strikingly, in cell viability studies monotherapy with an anti ADAM17 antibody had a significant effect in reducing cell proliferation of these cells and an additive effect in trastuzumab treatment. Furthermore, ADAM10 inhibition had only little effects, indicating that these cells may rely on HER3 activation through heregulin release by ADAM17. Thus, ADAM17 may play a key role in trastuzumab resistance in HER2 moderately expressing breast cancer cells. Our results suggest that in those cells, ADAM17 results in HER ligand sheddase which in turn may lead to the activation of HER receptors and the maintenance of pHER2. We demonstrated that an anti ADAM17 antibody is able to decrease pHER2, pHER3, as well as pPKB and is effective as monotherapy and additive to trastuzumab treatment in HER2 2+ breast cancer cells. We recommend that inhibition of ADAM17 with or without trastuzumab should be considered as a potential targeted therapy strategy in HER2 2+ breast cancer patients. Disclosure G. Murphy: The anti ADAM17 antibody was developed by Prof. Murphy's laboratory. Please see: Tape et al. Cross-domain inhibition of TACE ectodomain. Proc Natl Acad Sci USA 2011; 108(14):5578-83. All other authors have declared no conflicts of interest.