biostudies-literatureLitvin OHoward Hughes Medical InstituteNCI NIH HHSNIH HHS784-796https://www.ebi.ac.uk/biostudies/studies/S-EPMC4355234biostudies-literatureUnknown57(5)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 IFN?/? 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.Molecular cellInterferon ?/? Enhances the Cytotoxic Response of MEK Inhibition in Melanoma.PMC43552341U54CA121852-01A1R01CA164729DP2 OD002414U54 CA121852R01 CA164729Schwartz SSchild TChen BJPe'er DPratilas CGoddard NRocco MWan ZLitvin OOh NLfalseInterferon ?/? Enhances the Cytotoxic Response of MEK Inhibition in Melanoma.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 IFN?/? 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.2015-01-01T00:00:00Z2015 Mar2020-11-19T15:31:08Z2019-03-27T01:47:57ZS-EPMC43552342568420710.1016/j.molcel.2014.12.030