HER3 mediates metabolic reprogramming in metastatic colorectal and pancreatic cancer

Liver metastases are a major cause of mortality in colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC), yet the oncogenic signals that shape tumor metabolism in the hepatic niche remain poorly understood. Here, we show that HER3 activation drives a liver metastasis-specific glycolytic program in both cancer types. Genetic or pharmacological HER3 inhibition suppresses cancer glycolysis while increasing dependence on oxidative phosphorylation (OXPHOS), rendering liver metastases vulnerable to OXPHOS inhibition. Combining the HER3 inhibitor sapitinib with distinct OXPHOS inhibitors led to in vitro synergy and durable tumor-free survival in orthotopic CRC and PDAC liver metastases models, with further validation in patient-derived xenografts. Mechanistically, HER3 promotes glycolysis through activating PFK2 and reduces OXPHOS through activating DRP1-mediated mitochondrial remodeling, both pathways were activated in liver metastases compared to matched primary tumors. Together, our findings identify the HER3-AKT/RSK-PFK2 axis as a driver of glycolysis and metastatic growth and reveal an OXPHOS dependency induced by HER3 inhibition that may be exploited through combined HER3 and OXPHOS targeting in metastatic CRC and PDAC.