title: Functional genomics reveals diverse cellular processes that modulate tumor cell response to oxaliplatin.
abstract: Oxaliplatin is widely used to treat colorectal cancer, as both adjuvant therapy for resected disease and palliative treatment of metastatic disease. However, a significant number of patients experience serious side effects, including prolonged neurotoxicity, from oxaliplatin treatment creating an urgent need for biomarkers of oxaliplatin response or resistance to direct therapy to those most likely to benefit. As a first step to improve selection of patients for oxaliplatin-based chemotherapy, we have conducted an in vitro cell-based small interfering RNA (siRNA) screen of 500 genes aimed at identifying genes whose loss of expression alters tumor cell response to oxaliplatin. The siRNA screen identified twenty-seven genes, which when silenced, significantly altered colon tumor cell line sensitivity to oxaliplatin. Silencing of a group of putative resistance genes increased the extent of oxaliplatin-mediated DNA damage and inhibited cell-cycle progression in oxaliplatin-treated cells. The activity of several signaling nodes, including AKT1 and MEK1, was also altered. We used cDNA transfection to overexpress two genes (LTBR and TMEM30A) that were identified in the siRNA screen as mediators of oxaliplatin sensitivity. In both instances, overexpression conferred resistance to oxaliplatin. In summary, this study identified numerous putative predictive biomarkers of response to oxaliplatin that should be studied further in patient specimens for potential clinical application. Diverse gene networks seem to influence tumor survival in response to DNA damage by oxaliplatin. Finally, those genes whose loss of expression (or function) is related to oxaliplatin sensitivity may be promising therapeutic targets to increase patient response to oxaliplatin.
authors.affiliation: Genomic Health, Inc., 301 Penobscot Drive, Redwood City, CA 94063, USA.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Harradine
authors.forename: Michelle
authors.initials: M
authors.lastname: Kassner
authors.forename: Donald
authors.initials: D
authors.lastname: Chow
authors.forename: Meraj
authors.initials: M
authors.lastname: Aziz
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Von Hoff
authors.forename: Joffre B
authors.initials: JB
authors.lastname: Baker
authors.forename: Hongwei
authors.initials: H
authors.lastname: Yin
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Pelham
mesh_terms: D001686:Biological Phenomena / Q000187:drug effects / Q000235:genetics*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D052138:Genes, Neoplasm / Q000235:genetics; D023281:Genomics / Q000379:methods*; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D034741:RNA, Small Interfering / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D009944:Organoplatinum Compounds; D034741:RNA, Small Interfering; D000077150:Oxaliplatin