Targeted activation of ferroptosis in colorectal cancer via LGR4 targeting overcomes acquired drug resistance
Menée à l'aide de lignées cellulaires, d'organoïdes et d'échantillons de tumeurs colorectales, cette étude met en évidence un mécanisme par lequel le ciblage des voies de signalisation Wnt, via un anticorps monoclonal anti-récepteur LGR4, augmente la ferroptose et lève la chimiorésistance acquise lors de l'exposition répétée à de faibles doses d'agents chimiothérapeutiques
Acquired drug resistance is a major challenge for cancer therapy and is the leading cause of cancer mortality; however, the mechanisms of drug resistance are diverse and the strategy to specifically target drug-resistant cancer cells remains an unmet clinical issue. Here, we established a colorectal cancer-derived organoid biobank and induced acquired drug resistance by repeated low-level exposures of chemo-agents. Chemosensitivity profiling and transcriptomic analysis studies revealed that chemoresistant cancer-derived organoids exhibited elevated expression of LGR4 and activation of the Wnt signaling pathway. Further, we generated a monoclonal antibody (LGR4-mAb) that potently inhibited LGR4–Wnt signaling and found that treatment with LGR4-mAb notably sensitized drug-induced ferroptosis. Mechanistically, LGR4-dependent Wnt signaling transcriptionally upregulated SLC7A11, a key inhibitor of ferroptosis, to confer acquired drug resistance. Our findings reveal that targeting of Wnt signaling by LGR4-mAb augments ferroptosis when co-administrated with chemotherapeutic agents, demonstrating a potential opportunity to fight refractory and recurrent cancers.
Nature Cancer 2024