RETRACTED ARTICLE: Targeted activation of ferroptosis in colorectal cancer via LGR4 targeting overcomes acquired drug resistance
摘要
Acquired drug resistance is a major challenge for cancer therapy and isthe leading cause of cancer mortality; however, the mechanisms of drug resistanceare diverse and the strategy to specifically target drug-resistant cancer cellsremains an unmet clinical issue. Here, we established a colorectal cancer-derivedorganoid biobank and induced acquired drug resistance by repeated low-levelexposures of chemo-agents. Chemosensitivity profiling and transcriptomic analysisstudies revealed that chemoresistant cancer-derived organoids exhibited elevatedexpression of LGR4 and activation of the Wnt signaling pathway. Further, wegenerated a monoclonal antibody (LGR4-mAb) that potently inhibited LGR4–Wntsignaling and found that treatment with LGR4-mAb notably sensitized drug-inducedferroptosis. Mechanistically, LGR4-dependent Wnt signaling transcriptionallyupregulated SLC7A11, a key inhibitor of ferroptosis, to confer acquired drugresistance. Our findings reveal that targeting of Wnt signaling by LGR4-mAb augmentsferroptosis when co-administrated with chemotherapeutic agents, demonstrating apotential opportunity to fight refractory and recurrent cancers.