title: Gene expression signature of human cancer cell lines treated with the ras inhibitor salirasib (S-farnesylthiosalicylic acid).
abstract: Deregulation of Ras pathways results in complex abnormalities of multiple signaling cascades that contribute to human malignancies. Ras is therefore considered an appropriate target for cancer therapy. In light of the complexity of the deregulated Ras pathway, it is important to decipher at the molecular level the response of cancer cells to Ras inhibitors that would reregulate it. In the present study, we used gene expression profiling as a robust method for the global dissection of gene expression alterations that resulted from treatment with the Ras inhibitor S-farnesylthiosalicylic acid (FTS; salirasib). Use of a ranking-based procedure, combined with functional analysis and promoter sequence analysis, enabled us to decipher the common and most prominent patterns of the transcriptional response of five different human cancer cell lines to FTS. Remarkably, the analysis identified a distinctive core transcriptional response to FTS that was common to all cancer cell lines tested. This signature fits well to a recently described deregulated Ras pathway signature that predicted sensitivity to FTS. Taken together, these studies provide strong support for the conclusion that FTS specifically reregulates defective Ras pathways in human tumor cells. Ras pathway reregulation by FTS was manifested by repression of E2F-regulated and NF-Y-regulated genes and of the transcription factor FOS (all of which control cell proliferation), repression of survivin expression (which blocks apoptosis), and induction of activating transcription factor-regulated and Bach2-regulated genes (which participate in translation and stress responses). Our results suggest that cancer patients with deregulated Ras pathway tumors might benefit from FTS treatment.
authors.affiliation: Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Roy
authors.initials: R
authors.lastname: Blum
authors.forename: Ran
authors.initials: R
authors.lastname: Elkon
authors.forename: Shira
authors.initials: S
authors.lastname: Yaari
authors.forename: Adi
authors.initials: A
authors.lastname: Zundelevich
authors.forename: Jasmine
authors.initials: J
authors.lastname: Jacob-Hirsch
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
authors.forename: Ron
authors.initials: R
authors.lastname: Shamir
authors.forename: Yoel
authors.initials: Y
authors.lastname: Kloog
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D015536:Down-Regulation / Q000187:drug effects; D005204:Farnesol / Q000031:analogs & derivatives* / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012459:Salicylates / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D012459:Salicylates; C093323:farnesylthiosalicylic acid; D005204:Farnesol; D018631:ras Proteins