Versatile pathway-centric approach based on high-throughput sequencing to anticancer drug discovery

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 12; pp. 4609 - 4614
• Main Authors: Li, Hairi, Zhou, Hongyan, Wang, Dong, Qiu, Jinsong, Zhou, Yu, Li, Xiangqiang, Rosenfeld, Michael G, Ding, Sheng, Fu, Xiang-Dong
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 20.03.2012; National Acad Sciences
• Subjects: Androgen antagonists; androgen receptors; Androgens; Androgens - chemistry; Antigens - chemistry; antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis; Biological Sciences; Cardenolides - pharmacology; Cardiac glycosides; Cell growth; Cell Line, Tumor; Chemistry, Pharmaceutical - methods; cytotoxicity; Drug Design; Drug Screening Assays, Antitumor - methods; Gene expression; genes; Genetic screening; Genomics; Genotype & phenotype; glycosides; Glycosides - chemistry; high-throughput nucleotide sequencing; human diseases; Humans; Molecules; Phenotype; Preclinical drug evaluation; Prostate cancer; prostatic neoplasms; proteasome endopeptidase complex; Proteasome Endopeptidase Complex - chemistry; quantitative analysis; Research & development expenditures; RNA Interference; screening; Sequencing; T lymphocytes; therapeutics; transcription (genetics)
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1200305109

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 HTS2, 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.