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Updated: May 10, 2025
Subcellular Fractionation for ERK Activation Upon Mitochondrial-derived Peptide Treatment
Published on: September 25, 2017
Activation of the ERK1/2 Molecular Pathways and Its Relation to the Pathogenicity of Human Malignant Tumors
A G Emelyanova1,2, M A Zolotovskaia1,2, E V Poddubskaya2
1Moscow Institute of Physics and Technology, Dolgoprudny, 141701 Russian Federation.
Abstract:
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.
Insights
Mitogen-activated protein kinase ERK1/2 pathway activation impacts patient survival differently across cancer types. This finding offers new biomarkers for personalized cancer treatment strategies and drug development.
Area of Science:
- Oncology
- Molecular Biology
- Bioinformatics
Background:
- Mitogen-activated protein kinases, ERK1/2 (MAPK3/1), are crucial regulators of cell growth, differentiation, and apoptosis.
- ERK1/2 pathway activation in cancer cells can lead to drug resistance and overexpression of growth factor receptors.
- Previous research has established the role of ERK1/2 in cancer progression and therapeutic resistance.
Purpose of the Study:
- To algorithmically construct ERK1/2 molecular pathways and quantify their activation levels (PALs) using transcriptomic data.
- To investigate the impact of ERK1/2 PALs on patient survival and response to targeted therapies across various cancer types.
- To explore the potential of ERK1/2 pathway activation as a biomarker for predicting clinical outcomes and guiding personalized treatment strategies.
Main Methods:
- Utilized a novel bioinformatic technique to construct interactome network-based molecular pathways.
- Analyzed high-throughput gene expression data from 11,287 human tumor profiles across 31 cancer types.
- Correlated ERK1/2 pathway activation levels with patient survival data and response to 29 different chemotherapy and targeted therapy regimens.
Main Results:
- ERK1/2 pathway activation demonstrated varying prognostic significance across different cancer types.
- Worse survival was associated with ERK pathway activation in glioblastoma, sarcoma, lung, kidney, bladder, gastric, and colon cancers.
- Better survival was linked to ERK pathway activation in HER2+, luminal A and B breast cancers, and uterine corpus cancer.
- Treatment response analysis corroborated the survival trends.
- Expression levels of individual MAPK1 and MAPK3 genes showed significantly worse associations compared to pathway activation levels.
Conclusions:
- ERK1/2 pathway activation levels serve as potential biomarkers for predicting patient outcomes in various cancers.
- The prognostic significance of ERK1/2 pathway activation is cancer-type dependent.
- These findings support the development of personalized treatment strategies, including the use of MAPK inhibitors.
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