Gene expression-based chemical genomics identifies heat-shock protein 90 inhibitors as potential therapeutic drugs in cholangiocarcinoma.
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.
Institute of Clinical Medicine, National Yang-Ming University, and Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Ming-Huang
MH
Chen
Kun-Ju
KJ
Lin
Wu-Lung R
WL
Yang
Ya-Wen
YW
Kao
Tsung-Wen
TW
Chen
Shu-Chaou
SC
Chao
Peter Mu-Hsin
PM
Chang
Chun-Yu
CY
Liu
Cheng-Hwai
CH
Tzeng
Yee
Y
Chao
Ming-Han
MH
Chen
Chun-Nan
CN
Yeh
Chi-Ying F
CY
Huang
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000008:administration & dosage / Q000494:pharmacology*; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000378:metabolism*; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000235:genetics / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D020128:Inhibitory Concentration 50; D007555:Isoxazoles / Q000008:administration & dosage / Q000494:pharmacology*; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000494:pharmacology*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012118:Resorcinols / Q000008:administration & dosage / Q000494:pharmacology*; D059467:Transcriptome; D047368:Tumor Burden / Q000187:drug effects
C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D047029:Lactams, Macrocyclic; D012118:Resorcinols; C112765:tanespimycin