KRAS inhibitors may prevent colorectal cancer metachronous metastasis by suppressing TGF‑β mediated epithelial‑mesenchymal transition

Abstract

in colorectal cancer (crc), KraS mutations enhance metachronous metastasis, a condition without prognostic biomarkers or preventive measures. The present study demonstrated that KraS mutation may be a risk factor for crc metachronous metastasis through meta-analysis of public databases. a risk scoring model was constructed using machine learning for predicting metachronous metastasis in KraS-mutant crc. Wound healing and Transwell assay indicated that KraS inhibitors strongly suppress migration and invasion capabilities of high-risk CRC cells and these findings were validated through ex vivo organoid and a mouse model of splenic-liver metastasis. Mechanistically, rna sequencing, reverse transcription-quantitative Pcr and western blot analyses revealed that KraS inhibitors suppressed epithelial-mesenchymal transition (eMT) and transforming growth factor β (TGF-β) signaling. notably, addition of TGF-β1 protein partially reversed the inhibitory effects of KraS inhibitors on crc. These results suggested that KraS inhibitors may prevent crc metachronous metastasis by downregulating TGF-β-mediated eMT, suggesting they can be used prophylactically in high-risk KraS-mutant crc.