The significance of the activating transcription factor 6 gene in the pathogenesis of drug resistant cancer

Abstract

Chemotherapy remains a cornerstone in cancer therapy, but its effectiveness is often hindered by the development of drug resistance, a significant factor contributing to over 90 % of cancer-related deaths worldwide. A critical aspect of this resistance involves chronic endoplasmic reticulum stress, which activates the unfolded protein response (UPR), mainly through the activation of Activating Transcription Factor 6 (ATF6). Elevated ATF6 expression has been found to correlate with poor survival outcomes and increased resistance to chemotherapy across several malignancies. This study specifically investigates the role of ATF6 in cancer pathogenesis, focusing on its involvement in resistance mechanisms and the progression of the disease. Given the complex interactions between the UPR and other cellular pathways, including the DNA damage response (DDR), our findings emphasize the potential of targeting ATF6 and UPR and DDR pathways as a novel therapeutic strategy. This approach could potentially overcome chemoresistance and improve outcomes in cancer treatment. © 2025 Elsevier Ltd