Gene expression-based chemical genomics identifies heat-shock protein 90 inhibitors as potential therapeutic drugs in cholangiocarcinoma

Authors

  • Ming-Huang Chen MD,

    1. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
    2. Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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  • Kun-Ju Lin MD,

    1. Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
    2. Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan, Taiwan
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  • Wu-Lung R. Yang,

    1. Department of Computer Science and Information Engineering, National Taiwan University, Taipei, Taiwan
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  • Ya-Wen Kao,

    1. Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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  • Tsung-Wen Chen,

    1. Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
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  • Shu-Chaou Chao,

    1. Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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  • Peter Mu-Hsin Chang MD,

    1. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
    2. Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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  • Chun-Yu Liu MD,

    1. Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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  • Cheng-Hwai Tzeng MD,

    1. Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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  • Yee Chao MD,

    1. Department of Medicine, Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan
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  • Ming-Han Chen MD,

    1. Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
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  • Chun-Nan Yeh MD,

    Corresponding author
    1. Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
    • Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan

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    • Fax: (011) 886-33285818

  • Chi-Ying F. Huang

    Corresponding author
    1. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
    2. Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan
    • Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan

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    • Fax: (011) 886-228224045


Abstract

BACKGROUND.

Cholangiocarcinoma (CCA) is an aggressive tumor with a poor prognosis. There is no standard therapy for CCA, and novel drugs for treating refractory CCA need to be identified.

METHODS.

The authors hypothesized that, if a drug could reverse the gene expression signature of CCA, then it may inhibit the carcinogenesis of CCA and, hence, would be a potential therapeutic agent. Thus, the gene expression signatures from patients with CCA were queried using the bioinformatic method Connectivity Map, resulting in the enrichment of heat-shock protein 90 (HSP90) inhibitors with therapeutic potentials.

RESULTS.

Two HSP90 inhibitors, 17-AAG (tanespimycin) and the synthetic diarylisoxazole amide resorcinol NVP-AUY922, demonstrated potent antiproliferative activity in in vitro studies. In a thioacetamide-induced animal model, NVP-AUY922 also had antitumor activity and resulted in objective tumor regression. In addition, NVP-AUY922 reduced the expression of client oncoproteins involved in CCA oncogenesis and inhibited downstream proteins of both the phosphatidylinositol 3-kinase catalytic subunit α/v-akt murine thymoma viral oncogene homolog 1 protein kinase (PIK3/AKT) pathway and the v-Ki-ras2 Kirsten rat sarcoma viral oncogene/mitogen-activated protein kinase (KRAS/MAPK) pathway.

CONCLUSIONS.

Preclinical data from the current study suggest that NVP-AUY922 may be an effective treatment option for patients with CCA. Cancer 2013. © 2012 American Cancer Society.

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