Synthetic lethal screen identification of chemosensitizer loci in cancer cells

• Published in: Nature Vol. 446; no. 7137; pp. 815 - 819
• Main Authors: Peyton, Michael, Bodemann, Brian O, Minna, John D, Hao, Weihua, Ferguson, Deborah, White, Michael A, Xie, Xian-Jin, Cardenas, Jessica, Roth, Michael G, Girard, Luc, Michnoff, Carolyn, Whitehurst, Angelique W
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 12.04.2007; Nature Publishing Group
• Subjects: Algorithms; Antineoplastic agents; Apoptosis; Biological and medical sciences; Cancer; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Cell Survival - drug effects; Cellular biology; DNA Mutational Analysis; Dose-Response Relationship, Drug; General aspects; Genes, Lethal - genetics; Genomics; Humans; Lung - drug effects; Lung - metabolism; Lung - pathology; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Medical sciences; Microtubules - drug effects; Microtubules - metabolism; Mitosis - drug effects; Paclitaxel - pharmacology; Pathology; Pharmacology. Drug treatments; Proteins; Ribonucleic acid; RNA; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Spindle Apparatus - drug effects; Spindle Apparatus - metabolism; Spindle Apparatus - pathology; Tumors; Antineoplastic agent; Human; Lung disease; Respiratory disease; Malignant tumor; non-small cell lung carcinoma; Gene; Taxane derivatives; Established cell line; Paclitaxel; Chemosensitivity; Bronchus disease; Genetics; Locus; Antimitotic
• ISSN: 0028-0836; 1476-4687; 1476-4679
• DOI: 10.1038/nature05697

Abundant evidence suggests that a unifying principle governing the molecular pathology of cancer is the co-dependent aberrant regulation of core machinery driving proliferation and suppressing apoptosis. Anomalous proteins engaged in support of this tumorigenic regulatory environment most probably represent optimal intervention targets in a heterogeneous population of cancer cells. The advent of RNA-mediated interference (RNAi)-based functional genomics provides the opportunity to derive unbiased comprehensive collections of validated gene targets supporting critical biological systems outside the framework of preconceived notions of mechanistic relationships. We have combined a high-throughput cell-based one-well/one-gene screening platform with a genome-wide synthetic library of chemically synthesized small interfering RNAs for systematic interrogation of the molecular underpinnings of cancer cell chemoresponsiveness. NCI-H1155, a human non-small-cell lung cancer line, was employed in a paclitaxel-dependent synthetic lethal screen designed to identify gene targets that specifically reduce cell viability in the presence of otherwise sublethal concentrations of paclitaxel. Using a stringent objective statistical algorithm to reduce false discovery rates below 5%, we isolated a panel of 87 genes that represent major focal points of the autonomous response of cancer cells to the abrogation of microtubule dynamics. Here we show that several of these targets sensitize lung cancer cells to paclitaxel concentrations 1,000-fold lower than otherwise required for a significant response, and we identify mechanistic relationships between cancer-associated aberrant gene expression programmes and the basic cellular machinery required for robust mitotic progression.