Integrated functional, gene expression and genomic analysis for the identification of cancer targets

• Published in: PloS one 2009-04, Vol.4 (4), p.e5120-e5120
• Main Authors: Iorns, Elizabeth, Lord, Christopher J, Grigoriadis, Anita, McDonald, Sarah, Fenwick, Kerry, Mackay, Alan, Mein, Charles A, Natrajan, Rachael, Savage, Kay, Tamber, Narinder, Reis-Filho, Jorge S, Turner, Nicholas C, Ashworth, Alan
• Format: Article
• Language: English
• Subjects: Analysis; Biotechnology; Breast cancer; Cancer; Cancer genetics; Cell Cycle Proteins - genetics; Cell Line, Tumor; Cell survival; Class I Phosphatidylinositol 3-Kinases; Drug approval; Drug Screening Assays, Antitumor; Endocrine therapy; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes; Genetic aspects; Genetic research; Genetics and Genomics/Cancer Genetics; Genetics and Genomics/Functional Genomics; Genome; Genomes; Genomic analysis; Genomics; Health aspects; Humans; Identification; Kinases; Ligands; Lung cancer; Medical research; Medical screening; Molecular Sequence Data; Multiple myeloma; Mutation; Neoplasm Proteins - genetics; Neoplasms - genetics; Neoplasms - therapy; Nuclear Proteins - genetics; Oligonucleotide Array Sequence Analysis; Oncology; Phosphatidylinositol 3-Kinases - genetics; Phosphotransferases; Protein-Tyrosine Kinases - genetics; Ribonucleic acid; RNA; RNA Interference; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; RNA-mediated interference; Target recognition; Tumor cell lines; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0005120

The majority of new drug approvals for cancer are based on existing therapeutic targets. One approach to the identification of novel targets is to perform high-throughput RNA interference (RNAi) cellular viability screens. We describe a novel approach combining RNAi screening in multiple cell lines with gene expression and genomic profiling to identify novel cancer targets. We performed parallel RNAi screens in multiple cancer cell lines to identify genes that are essential for viability in some cell lines but not others, suggesting that these genes constitute key drivers of cellular survival in specific cancer cells. This approach was verified by the identification of PIK3CA, silencing of which was selectively lethal to the MCF7 cell line, which harbours an activating oncogenic PIK3CA mutation. We combined our functional RNAi approach with gene expression and genomic analysis, allowing the identification of several novel kinases, including WEE1, that are essential for viability only in cell lines that have an elevated level of expression of this kinase. Furthermore, we identified a subset of breast tumours that highly express WEE1 suggesting that WEE1 could be a novel therapeutic target in breast cancer. In conclusion, this strategy represents a novel and effective strategy for the identification of functionally important therapeutic targets in cancer.