Optimized transcriptional signature for evaluation of MEK/ERK pathway baseline activity and long-term modulations in ovarian cancer

Abstract

ABSTRACTOvarian cancer is the most aggressive and lethal of all gynecologic malignancies. High activity of the MEK/ERK signaling pathway is tightly associated with tumor growth, high recurrence rate, and treatment resistance. Several transcriptional signatures were proposed recently for evaluation of MEK/ERK activity in tumor tissue. In the present study, we validated the performance of a robust multi-cancer MPAS 10-gene signature in various experimental models and publicly available sets of ovarian cancer samples. Expression of four MPAS genes (PHLDA1, DUSP4, EPHA2, andSPRY4) displayed reproducible responses to MEK/ERK activity modulations across several experimental modelsin vitroandin vivo. Levels ofPHLDA1, DUSP4, andEPHA2expression were also significantly associated with baseline levels of MEK/ERK pathway activity in multiple human ovarian cancer cell lines and ovarian cancer patient samples available from the TCGA database. HighEPHA2expression, platinum therapy resistance, and advanced age at diagnosis were associated with poor overall patient survival. Taken together, our results demonstrate that performance of transcriptional signatures is significantly affected by tissue specificity and aspects of particular experimental models. We therefore propose that gene expression signatures derived from comprehensive multi-cancer studies should be always validated for each cancer type.