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Gene expression‐based chemical genomics identifies heat‐shock protein 90 inhibitors as potential therapeutic drugs in cholangiocarcinoma
Author(s) -
Chen MingHuang,
Lin KunJu,
Yang WuLung R.,
Kao YaWen,
Chen TsungWen,
Chao ShuChaou,
Chang Peter MuHsin,
Liu ChunYu,
Tzeng ChengHwai,
Chao Yee,
Chen MingHan,
Yeh ChunNan,
Huang ChiYing F.
Publication year - 2012
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.27743
Subject(s) - protein kinase b , cancer research , carcinogenesis , oncogene , medicine , kras , heat shock protein , cancer , crizotinib , mapk/erk pathway , palbociclib , kinase , biology , gene , signal transduction , colorectal cancer , cell cycle , biochemistry , pathology , breast cancer , lung cancer , malignant pleural effusion , metastatic breast cancer
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.