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

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.