Article révisé par les pairs
Résumé : Colorectal cancer (CRC) remains the second leading cause of cancer-relateddeaths worldwide, with its incidence continuing to rise. Regorafenib, a multi-kinase inhibitor approved for palliative treatment, has been shown to extendsurvival in patients with metastatic CRC (mCRC) who have failed standardtherapies. However, its clinical benefit is limited to a subset of patients, is typicallyshort-lived, and is often accompanied by significant toxicity. The mechanismsby which CRC cells develop resistance to regorafenib remain incompletelyunderstood. In this study, we investigated the mechanisms of regorafenibresistance using a preclinical mouse colon organoid model. Transcriptomicanalysis of Apc wild-type and Apc-deficient organoids treated with regorafenibrevealed upregulation of epithelial-to-mesenchymal transition (EMT), alterationsin the secretome, and increased activation of phosphorylated Erk1/2. Notably,co-treatment with an autophagy inhibitor suppressed regorafenib-induced EMTand its associated secretory phenotype, leading to reduced cell proliferation andenhanced apoptosis in mouse organoids. The efficacy of this drug combinationwas further supported by cell viability assays in human CRC cell lines. In contrast,primary mouse colon fibroblasts exhibited greater resistance to both single-agent and combination regorafenib treatments. In summary, our findings usingan organoid model suggest that autophagy inhibition may represent a promisingstrategy to overcome chemoresistance to regorafenib in mCRC patients.

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