title: Hsp90 Inhibition Results in Glucocorticoid Receptor Degradation in Association with Increased Sensitivity to Paclitaxel in Triple-Negative Breast Cancer.
abstract: Targetable molecular drivers for triple-negative breast cancer (TNBC) have been difficult to identify; therefore, standard treatment remains limited to conventional chemotherapy. Recently, new-generation small-molecule Hsp90 inhibitors (e.g., ganetespib and NVP-AUY922) have demonstrated improved safety and activity profiles over the first-generation ansamycin class. In breast cancer, clinical responses have been observed in a subset of TNBC patients following ganetespib monotherapy; however, the underlying biology of Hsp90 inhibitor treatment and tumor response is not well understood. Glucocorticoid receptor (GR) activity in TNBC is associated with chemotherapy resistance. Here, we find that treatment of TNBC cell lines with ganetespib resulted in GR degradation and decreased GR-mediated gene expression. Ganetespib-associated GR degradation also sensitized TNBC cells to paclitaxel-induced cell death both in vitro and in vivo. The beneficial effect of the Hsp90 inhibitor on paclitaxel-induced cytotoxicity was reduced when GR was depleted in TNBC cells but could be recovered with GR overexpression. These findings suggest that GR-regulated anti-apoptotic and pro-proliferative signaling networks in TNBC are disrupted by Hsp90 inhibitors, thereby sensitizing TNBC to paclitaxel-induced cell death. Thus, GR+ TNBC patients may be a subgroup of breast cancer patients who are most likely to benefit from adding an Hsp90 inhibitor to taxane therapy.
authors: Department of Medicine-Hematology/Oncology, The University of Chicago, Chicago, IL, 60637, USA.
authors: Abena S
authors: AS
authors: Agyeman
authors: Department of Medicine-Hematology/Oncology, The University of Chicago, Chicago, IL, 60637, USA.
authors: Wesley J
authors: WJ
authors: Jun
authors: Synta Pharmaceuticals Corporation, Lexington, MA, 02421, USA.
authors: David A
authors: DA
authors: Proia
authors: Department of Medicine-Hematology/Oncology, The University of Chicago, Chicago, IL, 60637, USA.
authors: Caroline R
authors: CR
authors: Kim
authors: Department of Medicine-Hematology/Oncology, The University of Chicago, Chicago, IL, 60637, USA.
authors: Maxwell N
authors: MN
authors: Skor
authors: Department of Health Studies, The University of Chicago, Chicago, IL, 60637, USA.
authors: Masha
authors: M
authors: Kocherginsky
authors: Department of Medicine-Hematology/Oncology, The University of Chicago, Chicago, IL, 60637, USA. sconzen@medicine.bsd.uchicago.edu.|Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, 60637, USA. sconzen@medicine.bsd.uchicago.edu.|Department of Medicine, The University of Chicago, 900 East 57th Street, Chicago, IL, 60637, USA. sconzen@medicine.bsd.uchicago.edu.
authors: Suzanne D
authors: SD
authors: Conzen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D017239:Paclitaxel / Q000008:administration & dosage* / Q000627:therapeutic use; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D014230:Triazoles / Q000008:administration & dosage* / Q000494:pharmacology; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D011965:Receptors, Glucocorticoid; C533237:STA 9090; D014230:Triazoles; D017239:Paclitaxel