Taken together, the results suggest that (a) sorafenib itself does not affect HGF/c-Met signalling but inhibits ERK1/2/MAPK signalling by targeting RAF, and PI3K/AKT signalling by the ERK1/2/MAPK pathway or other mechanism(s); (b) HGF secreted by M2 macrophages activates HGF/c-Met signalling and the downstream ERK1/2/MAPK and PI3K/AKT pathways.52,53 Indeed, PI3K has been shown to be involved in sorafenib resistance in HCC.19,20. The gene discussed is MET; the disease is hepatocellular carcinoma.