Abstract 3668: Inhibition of HSP90 with NVP-AUY922 induces a synergistic effect in HER2-amplified, trastuzumab-resistant breast and gastric cancer

Abstract

Abstract Background: Heat Shock Protein 90 (HSP90) enables the activation of a large number of client proteins of which the most clinically validated is HER2. NVP-AUY922 is a a highly potent, non-geldamycin HSP90 inhibitor that has shown preliminary activity in HER2 positive metastatic breast cancer. To explore its potential clinical utility specifically in HER2 amplified gastric and breast cancers, we evaluated the effect of AUY922 alone and in combination with trastuzumab in both trastuzumab-sensitive and resistant in vitro and in vivo models. Methods: A panel of 16 human gastric and 45 breast cancer cell lines, with 3 and 13 HER2-amplified lines respectively, were exposed in vitro to AUY922 over various concentrations to generate dose response curves. In both breast and gastric cancer, we used cell lines and xenograft models with conditioned trastuzumab-resistance to investigate the efficacy of AUY922 alongside trastuzumab. In all in vivo experiments, trastuzumab was dosed at 10 mg/kg (IP; twice/week) and AUY922 at 50 mg/kg, (IP; 5 days on, 2 days off). Effects of this combination on downstream markers (HER2, AKT, ERK) were analyzed via western blot. Results: AUY922 was found to have potent anti-proliferative activity in the low nanomolar range (< 40 nM) for 59 of the 61 gastric and breast cancer cell lines tested. Additionally, in both gastric and breast cancer, HER2-amplified cells expressed greater sensitivity to the compound when compared to the HER2-negative cells. In conditioned trastuzumab-resistant cell line models, AUY922 continued to have potent activity and exhibited a synergistic effect with trastuzumab. The in vitro combination also induced greater decreases in HER2, induced a G0/G1 cell cycle arrest, and increased the rates of apoptosis. In a conditioned trastuzumab-resistant gastric cancer in vivo model (N87-Res), the combination of AUY922 and trastuzumab showed greater anti-tumor efficacy than either drug alone. Conclusions: These data suggest that AUY922 in combination with trastuzumab has unique efficacy in trastuzumab-resistant models. The combination of HSP90 inhibitors and trastuzumab represents a novel approach to the treatment of HER2 amplified cancers. Clinical trials combining AUY922 and trastuzumab in HER2 amplified breast and gastric cancers are currently ongoing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3668. doi:1538-7445.AM2012-3668