title: Versatile pathway-centric approach based on high-throughput sequencing to anticancer drug discovery.
abstract: The advent of powerful genomics technologies has uncovered many fundamental aspects of biology, including the mechanisms of cancer; however, it has not been appropriately matched by the development of global approaches to discover new medicines against human diseases. Here we describe a unique high-throughput screening strategy by high-throughput sequencing, referred to as HTS(2), to meet this challenge. This technology enables large-scale and quantitative analysis of gene matrices associated with specific disease phenotypes, therefore allowing screening for small molecules that can specifically intervene with disease-linked gene-expression events. By initially applying this multitarget strategy to the pressing problem of hormone-refractory prostate cancer, which tends to be accelerated by the current antiandrogen therapy, we identify Peruvoside, a cardiac glycoside, which can potently inhibit both androgen-sensitive and -resistant prostate cancer cells without triggering severe cytotoxicity. We further show that, despite transcriptional reprogramming in prostate cancer cells at different disease stages, the compound can effectively block androgen receptor-dependent gene expression by inducing rapid androgen receptor degradation via the proteasome pathway. These findings establish a genomics-based phenotypic screening approach capable of quickly connecting pathways of phenotypic response to the molecular mechanism of drug action, thus offering a unique pathway-centric strategy for drug discovery.
authors.affiliation: Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Hairi
authors.initials: H
authors.lastname: Li
authors.forename: Hongyan
authors.initials: H
authors.lastname: Zhou
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.forename: Jinsong
authors.initials: J
authors.lastname: Qiu
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.forename: Xiangqiang
authors.initials: X
authors.lastname: Li
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenfeld
authors.forename: Sheng
authors.initials: S
authors.lastname: Ding
authors.forename: Xiang-Dong
authors.initials: XD
authors.lastname: Fu
mesh_terms: D000728:Androgens / Q000737:chemistry; D000941:Antigens / Q000737:chemistry; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002298:Cardenolides / Q000494:pharmacology; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D023281:Genomics; D006027:Glycosides / Q000737:chemistry; D006801:Humans; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry; D034622:RNA Interference
chemical_list: D000728:Androgens; D000941:Antigens; D000970:Antineoplastic Agents; D002298:Cardenolides; D006027:Glycosides; C100098:cannogenin thevetoside; D046988:Proteasome Endopeptidase Complex