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Gene expression-based chemical genomics identifies heat-shock protein 90 inhibitors as potential therapeutic drugs in cholangiocarcinoma
Article first published online: 18 JUL 2012
Copyright © 2012 American Cancer Society
Volume 119, Issue 2, pages 293–303, 15 January 2013
How to Cite
Chen, M.-H., Lin, K.-J., Yang, W.-L. R., Kao, Y.-W., Chen, T.-W., Chao, S.-C., Chang, P. M.-H., Liu, C.-Y., Tzeng, C.-H., Chao, Y., Chen, M.-H., Yeh, C.-N. and Huang, C.-Y. F. (2013), Gene expression-based chemical genomics identifies heat-shock protein 90 inhibitors as potential therapeutic drugs in cholangiocarcinoma. Cancer, 119: 293–303. doi: 10.1002/cncr.27743
- Issue published online: 4 JAN 2013
- Article first published online: 18 JUL 2012
- Manuscript Accepted: 24 MAY 2012
- Manuscript Revised: 18 MAY 2012
- Manuscript Received: 4 APR 2012
- Connectivity Map;
- drug repurposing;
- heat-shock protein 90
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.
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.
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.
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.