ROS-mediated senescence and autophagy inhibition drive 5-FU/Aumolertinib synergy in colorectal cancer

Epidermal growth factor receptor (EGFR) is frequently overexpressed in colorectal cancer (CRC) and promotes tumor invasion and metastasis. Although 5-fluorouracil (5-FU) serves as a first-line CRC therapeutic, its clinical utility is constrained by dose-dependent toxicity. This study demonstrated that combining 5-FU with the EGFR inhibitor aumolertinib (AUM) synergistically suppressed CRC progression while reducing effective 5-FU doses. Transcriptomic and functional analyses linked this synergy to cellular senescence and autophagic flux blockade. Mechanistically, reactive oxygen species (ROS) accumulation drives senescence and autophagy inhibition, which inactivates the PI3K/AKT/mTOR pathway, thereby inhibiting CRC cell proliferation, invasion, and migration. Notably, ROS scavenging with N-acetylcysteine reversed these effects. The synergistic tumor growth inhibition was confirmed in HCT116 xenografts using low-dose combination therapy (5-FU 15 mg/kg + AUM 10 mg/kg). Collectively, these findings establish an ROS-dependent autophagic senescence axis as the molecular basis for 5-FU/AUM synergy, offering a novel strategic approach for CRC treatment.