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.