Inhibition of HSP90 with AUY922 Induces Synergy in HER2-Amplified Trastuzumab-Resistant Breast and Gastric Cancer

Abstract

HSP90 enables the activation of many client proteins of which the most clinically validated is HER2. NVP-AUY922, a potent HSP90 inhibitor, is currently in phase II clinical trials. To explore its potential clinical use in HER2-amplified breast and gastric cancers, we evaluated the effect of AUY922 alone and in combination with trastuzumab in both trastuzumab-sensitive and -resistant models. A panel of 16 human gastric and 45 breast cancer cell lines, including 16 HER2-amplified (3 and 13, respectively) cells, was treated with AUY922 over various concentrations. 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. Effects of this combination on downstream markers were analyzed via Western blot analysis. AUY922 exhibited potent antiproliferative activity in the low nanomolar range (<40 nmol/L) for 59 of 61 cell lines. In both histologies, HER2-amplified cells expressed greater sensitivity to AUY than HER2-negative cells. In conditioned trastuzumab-resistant models, AUY922 showed a synergistic effect with trastuzumab. In vitro, the combination induced greater decreases in HER2, a G 2 cell-cycle arrest, and increased apoptosis. In a trastuzumab-resistant gastric cancer xenograft model, the combination of AUY922 and trastuzumab showed greater antitumor efficacy than either drug alone. These data suggest that AUY922 in combination with trastuzumab has unique efficacy in trastuzumab-resistant models. The combination of HSP90 inhibition and direct HER2 blockade represents a novel approach to the treatment of HER2-amplified cancers and clinical trials based on the above data are ongoing.

Hsp90 inhibitor SY-016 induces G2/M arrest and apoptosis in paclitaxel-resistant human ovarian cancer cells

“…Recent studies have demonstrated apoptotic effects of Hsp90 inhibitors on human leukemia cells (20). Furthermore, cancer cell-specific apoptotic effects of Hsp90 inhibitors were documented in breast and colorectal cancer cells (21,22). These findings indicate that cell growth inhibition induced by Hsp90 inhibitors is mediated through an apoptosis-dependent mechanism.…”

89Zr-trastuzumab and 89Zr-bevacizumab PET to Evaluate the Effect of the HSP90 Inhibitor NVP-AUY922 in Metastatic Breast Cancer Patients

“…[4][5][6]. HER2 is a sensitive client protein of HSP90, which can be depleted by HSP90 inhibition with NVP-AUY922 in many different preclinical experiments including breast cancer models (7,8). HIF1a is the key factor involved in upregulating the transcription of VEGF-A in hypoxic cells (9).…”

Geldanamycin induces apoptosis in human gastric carcinomas by affecting multiple oncogenic kinases that have synergic effects with TNF-related apoptosis-inducing ligand

“…More importantly, gastric cancer is characterized by extremely low survival rates among patients (21). Numerous studies have suggested the importance of Hsp90 in the progression of gastric cancer (22)(23)(24). Certain small molecular inhibitors of Hsp90, including MPC-3100 (Myriad Pharmaceuticals, Salt Lake City, UT, USA), have demonstrated potential in the treatment of gastric cancer (25).…”