ROS confer resistance to 3TC in p53 mutant colorectal cancer by promoting autophagy and ER stress

This is the authors' abstract. We don't add key points for this paper.

Colorectal cancer (CRC) is among the most frequently diagnosed cancers globally. Lamivudine (3 TC), a nucleoside reverse transcriptase inhibitor (NRTI) commonly used for treating Human Immunodeficiency Virus (HIV) and Hepatitis B Virus (HBV), has recently demonstrated anticancer activity against p53-mutant CRC in Phase 2 clinical trials. However, the underlying mechanisms remain elusive. Our study revealed that 3 TC promotes the accumulation of reactive oxygen species (ROS), which potentially counters its anticancer efficacy in p53-mutant CRC cells. Furthermore, we observed that ROS induced by 3 TC stimulates autophagy independently of the protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway and also activates the activating transcription factor 4 (ATF4)-mediated endoplasmic reticulum (ER) stress pathway. By inhibiting autophagy and ER stress, the anticancer effect of 3 TC was enhanced. In summary, our findings demonstrate that ROS accumulation attenuates the anticancer efficacy of 3 TC by promoting autophagy and ER stress, providing novel insights into the molecular mechanisms underlying 3 TC's therapeutic role in p53-mutant CRC.