title: Synthetic lethal screening with small-molecule inhibitors provides a pathway to rational combination therapies for melanoma.
abstract: Recent data show that extracellular signals are transmitted through a network of proteins rather than hierarchical signaling pathways, suggesting that the inhibition of a single component of a canonical pathway is insufficient for the treatment of cancer. The biologic outcome of signaling through a network is inherently more robust and resistant to inhibition of a single network component. In this study, we conducted a functional chemical genetic screen to identify novel interactions between signaling inhibitors that would not be predicted on the basis of our current understanding of signaling networks. We screened over 300 drug combinations in nine melanoma cell lines and have identified pairs of compounds that show synergistic cytotoxicity. The synergistic cytotoxicities identified did not correlate with the known RAS and BRAF mutational status of the melanoma cell lines. Among the most robust results was synergy between sorafenib, a multikinase inhibitor with activity against RAF, and diclofenac, a nonsteroidal anti-inflammatory drug (NSAID). Drug substitution experiments using the NSAIDs celecoxib and ibuprofen or the MAP-ERK kinase inhibitor PD325901 and the RAF inhibitor RAF265 suggest that inhibition of COX and mitogen-activated protein kinase signaling are targets for the synergistic cytotoxicity of sorafenib and diclofenac. Cotreatment with sorafenib and diclofenac interrupts a positive feedback signaling loop involving extracellular signal-regulated kinase, cellular phospholipase A2, and COX. Genome-wide expression profiling shows synergy-specific downregulation of survival-related genes. This study has uncovered novel functional drug combinations and suggests that the underlying signaling networks that control responses to targeted agents can vary substantially, depending on unexplored components of the cell genotype.
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Jordan Hall Rm 2-16, Box 800734, 1300 Jefferson Park Avenue, Charlottesville, VA 22908, USA.
authors.forename: Devin G
authors.initials: DG
authors.lastname: Roller
authors.forename: Mark
authors.initials: M
authors.lastname: Axelrod
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Capaldo
authors.forename: Karin
authors.initials: K
authors.lastname: Jensen
authors.forename: Aaron
authors.initials: A
authors.lastname: Mackey
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Weber
authors.forename: Daniel
authors.initials: D
authors.lastname: Gioeli
mesh_terms: D000970:Antineoplastic Agents / Q000032:analysis* / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004008:Diclofenac / Q000494:pharmacology / Q000627:therapeutic use; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use; D054510:Phospholipases A2, Cytosolic / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D054852:Small Molecule Libraries / Q000032:analysis* / Q000494:pharmacology* / Q000627:therapeutic use; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D054852:Small Molecule Libraries; D004008:Diclofenac; D009536:Niacinamide; D000077157:Sorafenib; D048049:Extracellular Signal-Regulated MAP Kinases; D054510:Phospholipases A2, Cytosolic