Activation of P38 MAPK Signaling Cascade is Linked with Clinical Outcomes and Therapeutic Responses in Human Cancers

Abstract

Activation of the p38 mitogen-activated protein kinase (MAPK) pathways is vital in regulating cell growth, differentiation, apoptosis, and stress response, significantly affecting tumorigenesis and cancer progression. We developed a bioinformatic technique to construct an interactome network-based molecular pathways for genes of interest and quantify their activation levels using high-throughput gene expression data. This study is focused on the p38α, p38β, p38γ, and p38δ kinases, examining their activation levels (PALs) based on transcriptomic data and their associations with survival and drug responsiveness across various cancer types. We analyzed 11,287 human tumor profiles from 31 cancer types and 53 datasets to assess patient survival and clinical response to 29 therapies. Activation of p38 pathways showed varying prognostic significance depending on the cancer type. In astrocytoma, glioblastoma, thymoma, renal, bladder, esophageal, colorectal, stomach cancers, and lung squamous cell carcinoma, p38 pathway activation correlated with poor survival. Conversely, it indicated better survival in the gender-associated tumors (HER2+, luminal A and B subtypes of breast cancer, prostate carcinoma), sarcomas, lung adenocarcinoma, and others. These trends are aligned with the response-to-therapy analysis. For instance, higher activation of the p38β and p38γ pathways was linked to positive responses to taxane and anthracycline therapies in breast cancer, while lower activation of the p38α and p38β pathways correlated with better responses to 5-fluorouracil-based treatments in colorectal cancer. However, associations with individual MAPK14, MAPK11, MAPK12, and MAPK13 gene expression levels were less robust. Hence, the p38 pathway activation levels could serve as potential biomarkers for predicting clinical outcomes and personalizing treatment strategies, including use of the selective p38 MAPK inhibitors.