Interferon α/β Enhances the Cytotoxic Response of MEK Inhibition in Melanoma

• Published in: Molecular cell 2015-03, Vol.57 (5), p.784-796
• Main Authors: Litvin, Oren, Schwartz, Sarit, Wan, Zhenmao, Schild, Tanya, Rocco, Mark, Oh, Nul Loren, Chen, Bo-Juen, Goddard, Noel, Pratilas, Christine, Pe’er, Dana
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Benzamides - pharmacology; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - genetics; Cluster Analysis; Diphenylamine - analogs & derivatives; Diphenylamine - pharmacology; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Humans; Interferon-alpha - pharmacology; Interferon-beta - pharmacology; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - genetics; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; Microphthalmia-Associated Transcription Factor - genetics; Microphthalmia-Associated Transcription Factor - metabolism; Models, Genetic; Mutation; Oligonucleotide Array Sequence Analysis; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - metabolism
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2014.12.030

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. [Display omitted] •Most targets of MAPK pathway are regulated by it only in a subset of cell lines•Cell lines with high activity of IFN pathway are resistant to MEK inhibition•IFNα/β treatment enhances the cytotoxic response of MEK inhibition•In resistant cells, CytoC is released but caspases are not cleaved Litvin et al. developed a computational method to identify targets of MAPK in melanoma and found that most genes are targets only in a subset of cell lines. They showed that interferon plays an important role in response to MAPK inhibition, and that IFNα/β enhances the effect of MEK inhibition.