| Summary: | Colorectal cancer (CRC) remains the third most frequently diagnosed cancer in the United States. The current treatment regimens for CRC include surgery followed by 5FU-based chemotherapy. Cancer stem-like cells (CSCs) have been implicated in 5FU-mediated chemoresistance, which leads to poor prognosis. In this study, we used metformin along with ICG-001, a Wnt signaling inhibitor, to abrogate CSC-mediated chemoresistance in CRC. We observed that 5FU-resistant (5FUR) CRC cells exhibited increased expression of CSC markers and enhanced spheroid formation. Genome-wide transcriptomic profiling analysis revealed that Wnt signaling, colorectal cancer metastasis signaling, etc., were enriched in 5FUR CRC cells. Accordingly, selective targeting of Wnt signaling using ICG-001 along with metformin abrogated CSC-mediated chemoresistance by decreasing the expression of CSC markers and promoting autophagy and apoptosis in a synergistic manner. We also observed that metformin and ICG-001 exhibited anti-tumor activity in CRC patient-derived tumor organoids. In conclusion, our study highlights that metformin and ICG-001 act synergistically and can be used as part of a therapeutic strategy to overcome 5FU-mediated therapeutic resistance in CRC.
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