title: 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 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.
authors: University of California Geffen School of Medicine, Department of Medicine, Division of Hematology/Oncology, Santa Monica, CA 90404, USA. zwainberg@mednet.ucla.edu
authors: Zev A
authors: ZA
authors: Wainberg
authors: Adrian
authors: A
authors: Anghel
authors: Amy M
authors: AM
authors: Rogers
authors: Amrita J
authors: AJ
authors: Desai
authors: Ondrej
authors: O
authors: Kalous
authors: Dylan
authors: D
authors: Conklin
authors: Raul
authors: R
authors: Ayala
authors: Neil A
authors: NA
authors: O'Brien
authors: Cornelia
authors: C
authors: Quadt
authors: Mikhail
authors: M
authors: Akimov
authors: Dennis J
authors: DJ
authors: Slamon
authors: Richard S
authors: RS
authors: Finn
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004357:Drug Synergism; D005260:Female; D005784:Gene Amplification; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D012118:Resorcinols / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D018719:Erb-b2 Receptor Tyrosine Kinases; D012118:Resorcinols; D000068878:Trastuzumab; C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide