title: Targeting heat-shock protein 90 with ganetespib for molecularly targeted therapy of gastric cancer.
abstract: Gastric cancer (GC) remains the fifth most common cancer worldwide. Heat-shock protein 90 (HSP90) has become an attractive therapeutic target in treating cancers, because of its abnormally high expression in cancers. Several successful cases of HSP90 inhibitors capable of inhibiting GC inspired us to try ganetespib, a clinically promising and actively investigated second-generation HSP90 inhibitor in GC treatment. In our study, we show that ganetespib markedly reduced the growth of MGC-803 and also significantly inhibited the growth of SGC-7901 and MKN-28 in a dose-dependent manner. It induced G2/M cell-cycle arrest and apoptosis in all three cell lines, together with the related markers affected significantly. Mechanistically, ganetespib caused pronounced decrease of expression of classic HSP90 client proteins. Specifically, it greatly affected epidermal growth factor receptor (EGFR) signaling cascades by markedly decreasing the levels of total EGFR and EGFR on cell membranes. EGFR knockdown also induced cell-cycle arrest and apoptosis accompanied with a decrease of several EGFR downstream proteins. These results strongly support that EGFR signaling greatly contributes to the ganetespib inhibitory effects. Besides, we found that the responses of GC cell lines to ganetespib correlated well with their EGFR expression levels: MGC-803, as well as AGS and BGC-803, with higher EGFR expression responded to ganetespib better, whereas SGC-7901 and MKN-28 with lower EGFR levels were much less sensitive to ganetespib. Although SGC-7901 and MKN-28 were not very sensitive to ganetespib, ganetespib worked synergistically with radiation and cisplatin in killing them. Importantly, ganetespib significantly inhibited the growth of xenograft tumors in vivo as a single agent or in combination with cisplatin. Results of hematoxylin/eosin staining, TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) assays, and immunohistochemistry staining of phosphorylated cyclin-dependent kinase 1 (pCDK1), EGFR and Ki-67 revealed significant differences in ganetespib-treated tumors. Collectively, our data suggest that ganetespib, as a new potent treatment option, can be used for the molecularly targeted therapy of GC patients according to their expression profiles of EGFR.
authors.affiliation: School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu 212013, China.
authors.forename: H
authors.identifier: 0000000179846305
authors.initials: H
authors.lastname: Liu
authors.affiliation: School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, China.
authors.forename: J
authors.initials: J
authors.lastname: Lu
authors.affiliation: Institute of Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212013, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Hua
authors.affiliation: School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu 212013, China.
authors.forename: P
authors.initials: P
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu 212013, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Liang
authors.affiliation: School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu 212013, China.
authors.forename: L
authors.initials: L
authors.lastname: Ruan
authors.affiliation: Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013, China.
authors.forename: C
authors.initials: C
authors.lastname: Lian
authors.affiliation: Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013, China.
authors.forename: H
authors.initials: H
authors.lastname: Shi
authors.affiliation: Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013, China.
authors.forename: K
authors.initials: K
authors.lastname: Chen
authors.affiliation: Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013, China.
authors.forename: Z
authors.identifier: 0000000198443245
authors.initials: Z
authors.lastname: Tu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D066246:ErbB Receptors / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D034741:RNA, Small Interfering / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018841:HSP90 Heat-Shock Proteins; D034741:RNA, Small Interfering; C533237:STA 9090; D014230:Triazoles; D066246:ErbB Receptors; D002945:Cisplatin