AUTOPHAGY INHIBITION IMPROVES SENSITIVITY TO THE MULTI-KINASE INHIBITOR REGORAFENIB IN PRECLINICAL MOUSE COLON TUMOROIDS

ABSTRACT: Colorectal cancer (CRC) remains the third leading cause of cancer-related deaths worldwide, with its incidence continuing to rise. Regorafenib, a multi-kinase inhibitor approved as a palliative treatment, extends survival in patients with metastatic CRC (mCRC) who have failed standard therapies. However, the clinical benefit of regorafenib is limited to a subset of patients, is typically short-lived, and is often accompanied by significant toxicity. The mechanisms by which CRC cells develop resistance to regorafenib remain poorly understood.In this study, we investigated resistance mechanisms to regorafenib using a preclinical mouse colon organoid model. Transcriptomic analysis of Apc wild-type and Apc-deficient organoids treated with regorafenib revealed an upregulation of epithelial-to-mesenchymal transition (EMT), accompanied by alterations in the secretome and increased activation of phosphorylated Erk1/2. Notably, co-treatment with an autophagy inhibitor suppressed regorafenib-induced EMT and its associated secretory phenotype, resulting in reduced cell proliferation and enhanced apoptosis in mouse organoids. The effectiveness of this drug combination was further supported by cell viability assays in human CRC cell lines. In contrast, primary mouse colon fibroblasts displayed greater resistance to both single-agent and combination regorafenib treatments. In summary, our findings using a preclinical organoid model suggest that autophagy inhibition may offer a promising strategy to mitigate chemoresistance and reduce toxicity associated with regorafenib treatment in mCRC patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE297312 | GEO | 2025/08/13

REPOSITORIES: GEO