American Association for Cancer Research
15357163mct120507-sup-supplementary_figure_3_pdf_file_-_58k.pdf (58.08 kB)

Supplementary Figure 3 from Inhibition of HSP90 with AUY922 Induces Synergy in HER2-Amplified Trastuzumab-Resistant Breast and Gastric Cancer

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journal contribution
posted on 2023-04-03, 13:47 authored by Zev A. Wainberg, Adrian Anghel, Amy M. Rogers, Amrita J. Desai, Ondrej Kalous, Dylan Conklin, Raul Ayala, Neil A. O'Brien, Cornelia Quadt, Mikhail Akimov, Dennis J. Slamon, Richard S. Finn

Supplementary Figure 3 PDF file - 58K, Activation of HSP70 in both N87-Parental and N87-TRC cell lines



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 G2 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. Mol Cancer Ther; 12(4); 509–19. ©2013 AACR.

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