title: Compensatory pathways induced by MEK inhibition are effective drug targets for combination therapy against castration-resistant prostate cancer.
abstract: Targeted therapies have often given disappointing results when used as single agents in solid tumors, suggesting the importance of devising rational combinations of targeted drugs. We hypothesized that construction of such combinations could be guided by identification of growth and survival pathways whose activity or expression become upregulated in response to single-agent drug treatment. We mapped alterations in signaling pathways assessed by gene array and protein phosphorylation to identify compensatory signal transduction pathways in prostate cancer xenografts treated with a MAP/ERK kinase (MEK) inhibitor PD325901. In addition to numerous components of the extracellular signal-regulated kinase (ERK) signaling pathway, components of the IKK, hedgehog, and phosphoinositide 3-kinase/Akt/mTOR pathways were upregulated following treatment with PD325901. Combinations of PD325901 with inhibitors of any one of these upregulated pathways provided synergistically greater growth inhibition of in vitro cell growth and survival than the individual drugs alone. Thus, the identification of compensatory signal transduction pathways paves the way for rational combinatorial therapies for the effective treatment of prostate cancer.
authors.affiliation: Department of Microbiology, PO Box 800734, University of Virginia Health System, Charlottesville, VA 22908, USA. dgg3f@virginia.edu
authors.forename: Daniel
authors.initials: D
authors.lastname: Gioeli
authors.forename: Winfried
authors.initials: W
authors.lastname: Wunderlich
authors.forename: Judith
authors.initials: J
authors.lastname: Sebolt-Leopold
authors.forename: Stefan
authors.initials: S
authors.lastname: Bekiranov
authors.forename: Julia D
authors.initials: JD
authors.lastname: Wulfkuhle
authors.forename: Emanuel F
authors.initials: EF
authors.lastname: Petricoin
authors.forename: Mark
authors.initials: M
authors.lastname: Conaway
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Weber
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D004357:Drug Synergism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; D047428:Protein Kinase Inhibitors; C506614:mirdametinib; D004159:Diphenylamine; D020929:Mitogen-Activated Protein Kinase Kinases