Cancer is a leading cause of death, with cancer metastasis being the main reason for cancer mortality due to low survival rates and lack of clinical therapy. Circulating tumor cells have been found to play a significant role in distal cancer metastasis, making them a potential target for clinical cancer therapy. Our preliminary study on Antrodia cinnamomea’s ubiquinone derivative, GKB202, showed promising results in inhibiting circulating tumor cells survival rates in oral, hepatocellular, and colorectal cancers. In this study, we examine the effect of GKB202 on pancreatic cancer patient-derived circulating tumor cells and explore the molecular mechanisms involved in circulating tumor cell using bioinformatics analysis of RNAseq. The results showed that GKB202 reduced endothelin-1 expression and down-regulated signaling cascades in pancreatic cancer patient-derived circulating tumor cells. Furthermore, GKB202 was found to have a secondary role in stopping the production of ET-1 in endothelial cells stimulated by cancer cells. Protein bioinformatics analysis predicted that the MAPK and AKT pathways regulate tumor angiogenesis, and this study suggested that GKB202 could reduce MAPK and AKT expression in endothelial cells induced by the cancer-conditioned medium, indicating its potential to inhibit circulating tumor cells and prevent the completion of the extravasation process. These findings suggest that targeting ET-1 receptors could provide a new approach to cancer treatment, and GKB202 could complement the current treatment arsenal against late-stage cancer patients diagnosed with circulating tumor cells.