Small molecule inhibitor screening identifified HSP90 inhibitor 17-AAG as potential therapeutic agent for gallbladder cancer

Abstract

Gallbladder cancer (GBC) is a lethal cancer with poor prognosis associated with high invasiveness and poor response to chemotherapy and radiotherapy. New therapeutic approaches are urgently needed in order to improve survival and response rates of GBC patients. We screened 130 small molecule inhibitors on a panel of seven GBC cell lines and identified the HSP90 inhibitor 17-AAG as one of the most potent inhibitory drugs across the different lines. We tested the antitumor efficacy of 17-AAG and geldanamycin (GA) in vitro and in a subcutaneous preclinical tumor model NOD-SCID mice. We also evaluated the expression of HSP90 by immunohistochemistry in human GBC tumors.In vitro assays showed that 17-AAG and GA significantly reduced the expression of HSP90 target proteins, including EGFR, AKT, phospho-AKT, Cyclin B1, phospho-ERK and Cyclin D1. These molecular changes were consistent with reduced cell viability and cell migration and promotion of G2/M cell cycle arrest and apoptosis observed in our in vitro studies.In vivo, 17-AAG showed efficacy in reducing subcutaneous tumors size, exhibiting a 69.6% reduction in tumor size in the treatment group compared to control mice (p < 0.05).The HSP90 immunohistochemical staining was seen in 182/209 cases of GBC (87%) and it was strongly expressed in 70 cases (33%), moderately in 58 cases (28%), and weakly in 54 cases (26%).Our pre-clinical observations strongly suggest that the inhibition of HSP90 function by HSP90 inhibitors is a promising therapeutic strategy for gallbladder cancer that may benefit from new HSP90 inhibitors currently in development.

Proteasome Inhibitors Suppress ErbB Family Expression through HSP90-Mediated Lysosomal Degradation

“…Consequently, the role of HSP90 in ErbB downregulation by proteasome inhibitors was then addressed. Treatments with both HSP90 inhibitor [39] and bortezomib [23,24] have been shown to inactivate HSP90α and increase its protein level. Our data also showed that the expression of HSP90α, but not full-length HSP90β, slightly increased when the cells were treated by proteasome inhibitors (Figure 4A,B), which might be because HSP90α mediates the fast chaperon response, while HSP90β is required the long-term cellular adaptation [40].…”

Functional genomic analysis identifies drug targetable pathways in invasive and metastatic cutaneous squamous cell carcinoma

“…( Supplemental Table 6 ). These panels have been used to identify kinase dependence in models of gallbladder cancer, nasopharyngeal carcinoma, and by us in leukemia and HNSCC ( Weber et al 2017 ; Yuan et al 2017 ; Tyner et al 2018 ).…”

“…(Supplemental Table 6). These panels have been used to identify kinase dependence in models of gallbladder cancer, nasopharyngeal carcinoma, and by us in leukemia and HNSCC (Weber et al 2017;Yuan et al 2017;Tyner et al 2018). Whole-exome sequencing (Illumina Hi-Seq) was performed on the three cases of collected samples with a median coverage of 209×-213×.…”

Sensitization of multidrug-resistant cancer cells to Hsp90 inhibitors by NSAIDs-induced apoptotic and autophagic cell death

“…Evidence of the activities of Hsp90 inhibitors has been obtained in vitro and in animal models, and numerous clinical trials (phase I-III) have been conducted to develop novel cancer treatments [ 2 – 5 ]. A number of phase II clinical trials have been performed on 17-allylamino-17-demethoxy-geldanamycin (17-AAG; a geldanamycin analog) and NVP-AUY922 (hereafter called AUY922; a purine-scaffold derivative and non-geldanamycin analog of 17-AAG) [ 6 – 9 ]. However, their therapeutic benefits were often limited by toxicity and resistance of cancer cells.…”