Work

The KRAS-G12D mutation drives venous thromboembolism (VTE) and colorectal cancer progression via MAPK/ERK signaling

Year: 2025

Type: article

Abstract: • Dual-purpose prognostic model: A novel KRAS-G12D-associated coagulation gene (KMCG) signature (PLCG2/MAPK12/C4B) stratifies CRC patients into high-risk groups with reduced survival (HR=3.44), elevated thrombotic risk, and enhanced immunotherapy sensitivity, integrating thrombogenesis and tumor progression prognostication. • Mechanistic dualism of KRAS-G12D: The mutation drives both cancer metastasis and thrombosis via MAPK/ERK pathway activation, inducing platelet hyperactivation, endothelial procoagulant transformation, and increased VTE incidence (clinically validated by elevated D-dimer levels). • Therapeutic axis validation: MAPK/ERK inhibition (U0126) concurrently attenuates thrombosis and metastasis in vivo, identifying a dual-targetable pathway to manage thrombotic complications and malignant progression in KRAS-mutant CRC. KRAS mutations occur in nearly 50 % of colorectal cancer (CRC) cases, with G12D representing the most frequent variant. While CRC is recognized as a moderate risk factor for venous thromboembolism (VTE), the thrombogenic potential of KRAS-G12D mutations remains poorly understood. We established a KRAS-G12D-associated coagulation gene (KMCG) prognostic model through integrative analysis of clinical data from CRC patients. Mechanistic investigations combining in vitro and in vivo models revealed that KRAS-G12D potentiates thrombotic risk through MAPK/ERK pathway activation. Integrating TCGA data, we constructed a KRAS-G12D-associated coagulation gene (PLCG2/MAPK12/C4B)-based prognostic model, where high-risk patients exhibited significantly reduced overall survival (HR=3.44) and superior 1-year AUC (0.718). Mechanistic profiling revealed high-risk enrichment in coagulation cascades, MAPK signaling, and immune infiltration, coupled with elevated tumor mutational burden (TMB) and immunotherapy sensitivity. Clinical validation confirmed KRAS-G12D mutation markedly increased D-dimer levelsand VTE incidence. Functional studies demonstrated mutant-driven platelet hyperactivation via MAPK/ERK pathway activation, evidenced by elevated aggregation rates and procoagulant endothelial transformation. In vivo, MAPK/ERK inhibitor U0126 attenuated thrombosis and metastasis, validating the pathway’s dual role in thrombogenesis and tumor progression. Our findings establish KMCG as a novel biomarker integrating thrombotic risk and tumor progression, while mechanistically linking KRAS-G12D-driven MAPK activation to both cancer metastasis and thrombosis. This dual regulatory axis provides therapeutic targets for simultaneously managing thrombotic complications and malignant progression in KRAS-mutant CRC.

Source: Translational Oncology

DOI: 10.1016/j.tranon.2025.102529