several colorectal cancer patient derived tumor organoid RNAseq data
Acquired drug resistance is a major challenge for cancer therapy and 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. We establisheda32 colorectal cancer (CRC) PDO biobank and induced acquired drug resistance by repeated low-level exposures of chemo-agents. Chemosensitivity profiling and transcriptomic analysis studies34 revealed that chemo-resistant PDOs exhibited elevated expression of LGR4 and activationof the35 Wnt signaling pathway. Further, we performed antibody screening against LGR4 and selecteda36 monoclonal antibody (LGR4-mAb) that potently inhibited the LGR4/Wnt signaling. In drug resistant PDOs and xenograft models, treatment with LGR4-mAb significantly sensitizeddrug- 38 induced ferroptosis. Mechanistically, LGR4 dependent Wnt signaling transcriptionally up-regulated SLC7A11, a key inhibitor of ferroptosis, to confer acquired drug resistance. Targeting40 Wnt signaling by LGR4-mAb and by other modulators augments ferroptosis when co-administrated with chemotherapeutic agents. Finally, LGR4-mAb therapy was effective against other cancers that express high levels of LGR4. Collectively, our results demonstrate a new strategy to selectively activate ferroptosis and provide a new opportunity to fight refractoryand44 recurrent cancers. Overall design: The IC50 of chemotherapy drugs 5-Fu and Cisplatin were detected by detecting tumor organoid from different patients, and the gene expression differences were compared in different groups.