Type I IFN Activity Predicts Response to MEK Inhibition in Melanoma

The majority of melanoma tumors exhibit perturbation of the MAPK signaling pathway, which has been shown to be an effective therapeutic target. However, individual patients display variable phenotypic responses to MAPK pathway inhibition due to mechanisms that are poorly understood. Litvin and colleagues developed a computational tool called context-specific regulation (COSPER) to characterize alterations in the transcriptional responses to MEK inhibition. Melanoma cell lines displayed phenotypic and transcriptional heterogeneity in response to MEK inhibition, with most genes regulated by MAPK signaling only in a subset of cell lines. Analysis of pre- and post-inhibition transcriptional data using COSPER identified context-specific gene clusters directly regulated by the MAPK pathway. Notably, the expression of a cluster containing several genes of the type I IFN pathway correlated with the cytotoxic response to MEK inhibition. This IFN cluster was split into two groups of cell lines delineated by low or high IFN–STAT1 activity. Cell lines with low STAT1 activity were sensitive to the cytotoxic response of MEK inhibition and exhibited increased cytotoxicity in response to combined treatment with IFNα/β; in contrast, cell lines with high STAT1 activity were resistant to both MEK inhibition and dual treatment, indicating a fundamental difference in therapeutic response between the two groups. Interestingly, although all cell lines underwent cytochrome c release following MEK inhibition, only cell lines with low STAT1 activity exhibited activation of the caspase pathway and induction of apoptosis. Furthermore, low IFN–STAT1 activity correlated with deletion of the IFN locus on chromosome 9p22 and low expression of IFN genes, whereas cell lines with high STAT1 activity harbored two or three copies of the 9p22 locus. These data suggest that the IFN pathway plays an important role in the cytotoxic response to MAPK-directed therapy in melanoma and demonstrate the utility of this approach for system-wide analyses of transcriptional programs to predict therapeutic response.

Litvin O, Schwartz S, Wan Z, Schild T, Rocco M, Oh NL, et al. Interferon α/β enhances the cytotoxic response of MEK inhibition in melanoma. Mol Cell 2015;57:784–96.

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