HER3 mediates metabolic reprogramming in metastatic colorectal and pancreatic cancer

HER3 activation drives a liver-metastasis–specific glycolytic program in metastatic colorectal cancer and pancreatic ductal adenocarcinoma, and HER3 inhibition shifts tumors toward OXPHOS dependence.

• Why it matters: Liver metastases cause major mortality in CRC and PDAC, but the hepatic signals that reprogram tumor metabolism were unclear.
• What they did: The study used genetic or pharmacological HER3 inhibition, then tested sapitinib plus OXPHOS inhibitors in orthotopic CRC and PDAC liver metastasis models and validated in patient-derived xenografts. Mechanistically, HER3 activated PFK2 and reduced OXPHOS via DRP1-mediated mitochondrial remodeling.
• The result: HER3 inhibition suppressed glycolysis and increased reliance on OXPHOS, and combining sapitinib with OXPHOS inhibitors produced in vitro synergy and durable tumor-free survival, suggesting HER3-AKT/RSK-PFK2–linked glycolysis can be targeted alongside OXPHOS.

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