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

Abstract

In colorectal cancer (CRC ), KRA S mutations enhance metachronous metastasis, a condition without prognostic biomarkers or preventive measures. The present study demonstrated that KRA S 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 KRA S-mutant CRC . Wound healing and Transwell assay indicated that KRA S 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 KRA S 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 KRA S inhibitors on CRC . These results suggested that KRA S inhibitors may prevent CRC metachronous metastasis by downregulating TGF-β-mediated EMT, suggesting they can be used prophylactically in high-risk KRA S-mutant CRC .