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Investigation on the molecular mechanisms of resistance to chemotherapy in Colorectal cancer

par Agostini, Giulia
Président du jury Lybaert, Pascale
Promoteur Garcia, Marie-Isabelle
Publication Non publié, 2026-07-09

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Résumé :

Chemotherapy resistance remains a major challenge in colorectal cancer (CRC), and the mechanisms driving reduced sensitivity are not fully understood. Regorafenib is one of the few approved treatments for patients with metastatic CRC, yet its clinical benefit is often limited by rapid development of resistance. In this study, we used a preclinical mouse colon organoid model consisting of Apc wild type and Apc deficient organoids to investigate the direct effects of regorafenib and to identify pathways that contribute to treatment resistance. Transcriptomic profiling demonstrated a consistent activation of epithelial–mesenchymal transition (EMT). We also observed induced pERK activation after treatment, and the secretome analysis revealed additional markers associated with poor prognosis in patients. Building on these findings, we explored a combinatorial strategy targeting autophagy, a mechanism highlighted by our transcriptomic data. Combining autogramin‑2 with regorafenib reduced EMT activation, decreased pERK signaling, and diminished secretion of resistance‑associated proteins, supporting the potential of this combination to overcome adaptive resistance. Human CRC cell lines were then used to validate the findings, and cell viability assays showed that autogramin 2 sensitized the cells to regorafenib treatment, supporting the relevance of the combinatorial strategy. However, when examining downstream signaling, we found that pERK behaved differently in the cell lines, displaying an opposite pattern compared with the mouse organoid model. Exploring the stromal contribution, primary fibroblasts were included in the analysis, and they also responded to regorafenib treatment, although they proved to be substantially more resistant to both the single agent and the combinational treatment. Together, our results provide new mechanistic insights into regorafenib resistance and highlight a promising combinatorial approach to improve treatment efficacy.