Pan-cancer chemoresistance-associated genes, affected pathways and potential therapeutic targets

Abstract

Background: Chemotherapy is one of the first-line treatment options for cancer. Chemotherapeutic agents exert their anti-cancer effects following different mechanisms. The prevalence of chemoresistance is substantially high worldwide. Resistance to chemotherapeutic agents increases the risk of cancer relapse and metastasis. In this study, we investigated the common chemoresistance-associated genes and pathways in different chemoresistant cancer cells that have been treated with various classes of chemotherapeutics. Method: We used in silico tools to investigate the chemoresistance-associated genes and pathways in 13 different cancer cell types (breast-, colon-, gastric-, ovarian-, pancreatic-, lung-, prostate cancer, chronic myeloid leukemia, hepatocellular-, head and neck squamous cell carcinoma, gestational trophoblastic neoplasia, multiple myeloma, and melanoma) treated with 10 different classes of chemotherapeutic drugs (anthracyclines, methotrexates, nucleoside analogues, cyclin-dependent kinase inhibitors, taxanes, tyrosine kinase inhibitors, platinum-based drugs, vinca alkaloids, proteasome inhibitor and topoisomerase I inhibitor) by analyzing 47 paired (control vs. chemoresistant) global gene expression datasets containing 620 individual samples. Results: We identified 43 differentially expressed genes associated with pan-cancer chemoresistance, among which 21 have significant regulatory roles. Furthermore, gene-disease associations revealed that 13 genes (SRC, PAK1, NFKBIA, ESR1, NFKB1, HRAS, MAPK1, PIK3CA, AURKA, MAPK3, PLCG1, PTPN11, and PRKCA) and associated pathways, particularly the Mitogen-Activated Protein Kinase (MAPK) signaling pathway, PI3K/Akt signaling pathway, JAK-STAT signaling pathway, and regulation of actin cytoskeleton, can heavily influence various cancers and chemoresistance in diverse ways. Conclusion: The findings from this study on chemoresistance-promoting genes and their mechanisms of action may be useful in the in vitro pursuit of common therapeutic targets for inhibiting chemoresistance in cancer cells.