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Mitogen-activated protein kinases, ERK1/2 (MAPK3/1), play a key role in the regulation of cell growth, differentiation, and apoptosis. We have previously presented evidence proving that activation of the ERK1/2 axis in cancer cells following the administration of therapeutics leads to the overexpression of growth factor receptors and drug resistance. Recently, we have proposed a new bioinformatic technique that enables direct construction of interactome network-based molecular pathways for gene products of interest, as well as quantitation of their activation levels using high-throughput gene expression data. In this study, we, for the first time, algorithmically constructed ERK1/2 molecular pathways and investigated how their activation levels (PALs) affect survival and responsiveness to targeted drugs at the pan-cancer level based on transcriptomic data. We examined a total of 11 287 human tumor profiles from 31 types of cancer, drawn from 53 of our previously published and other literature datasets, looking at patient survival and clinical response to 29 chemo- and targeted therapy regimens. We found that activation of the ERK1/2 pathways has different prognostic significance depending on cancer type. In glioblastoma, sarcoma, lung, kidney, bladder, gastric, colon, and several other cancer types, ERK pathway activation was associated with worse survival. In contrast, the same phenomenon was associated with a better chance of survival in HER2+, luminal A and luminal B breast cancer, and uterine corpus cancer. These trends were consistent with treatment response analysis. At the same time, we found significantly worse associations with the expression levels of individual MAPK1 and MAPK3 genes: hence, ERK1/2 pathway activation levels can be considered putative biomarkers for predicting clinical outcomes and selecting new personalized treatment strategies, such as the use of MAPK inhibitors.