title: Interferon α/β Enhances the Cytotoxic Response of MEK Inhibition in Melanoma.
abstract: Drugs that inhibit the MAPK pathway have therapeutic benefit in melanoma, but responses vary between patients, for reasons that are still largely unknown. Here we aim at explaining this variability using pre- and post-MEK inhibition transcriptional profiles in a panel of melanoma cell lines. We found that most targets are context specific, under the influence of the pathway in only a subset of cell lines. We developed a computational method to identify context-specific targets, and found differences in the activity levels of the interferon pathway, driven by a deletion of the interferon locus. We also discovered that IFNα/β treatment strongly enhances the cytotoxic effect of MEK inhibition, but only in cell lines with low activity of interferon pathway. Taken together, our results suggest that the interferon pathway plays an important role in, and predicts, the response to MAPK inhibition in melanoma. Our analysis demonstrates the value of system-wide perturbation data in predicting drug response.
authors: Department of Biological Sciences and Department of Systems Biology, Columbia University, 1212 Amsterdam Avenue, New York, NY 10027, USA.
authors: Oren
authors: O
authors: Litvin
authors: Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Sarit
authors: S
authors: Schwartz
authors: Department of Biological Sciences and Department of Systems Biology, Columbia University, 1212 Amsterdam Avenue, New York, NY 10027, USA.
authors: Zhenmao
authors: Z
authors: Wan
authors: Department of Biological Sciences and Department of Systems Biology, Columbia University, 1212 Amsterdam Avenue, New York, NY 10027, USA.
authors: Tanya
authors: T
authors: Schild
authors: Department of Biological Sciences and Department of Systems Biology, Columbia University, 1212 Amsterdam Avenue, New York, NY 10027, USA.
authors: Mark
authors: M
authors: Rocco
authors: Department of Biological Sciences and Department of Systems Biology, Columbia University, 1212 Amsterdam Avenue, New York, NY 10027, USA.
authors: Nul Loren
authors: NL
authors: Oh
authors: Department of Biological Sciences and Department of Systems Biology, Columbia University, 1212 Amsterdam Avenue, New York, NY 10027, USA.
authors: Bo-Juen
authors: BJ
authors: Chen
authors: Department of Biological Sciences and Department of Systems Biology, Columbia University, 1212 Amsterdam Avenue, New York, NY 10027, USA.
authors: Noel
authors: N
authors: Goddard
authors: Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Christine
authors: C
authors: Pratilas
authors: Department of Biological Sciences and Department of Systems Biology, Columbia University, 1212 Amsterdam Avenue, New York, NY 10027, USA. Electronic address: dpeer@biology.columbia.edu.
authors: Dana
authors: D
authors: Pe'er
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D016000:Cluster Analysis; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D016899:Interferon-beta / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism; D008957:Models, Genetic; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D016898:Interferon-alpha; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D050794:STAT1 Transcription Factor; D016899:Interferon-beta; C506614:mirdametinib; D004159:Diphenylamine