CT-707 overcomes hypoxia-mediated sorafenib resistance in Hepatocellular carcinoma by inhibiting YAP signaling

Background: Hepatocellular carcinoma (HCC) ranks among the leading causes of cancer-related mortality globally. Despite its status as a first-line treatment for advanced HCC, sorafenib’s efficacy remains limited, evidenced by low response rates and insufficient prolongation of progression-free survival (PFS). Therefore, there is an urgent need to explore strategies to enhance clinical outcomes.

Materials and Methods: We assessed the impact of sorafenib on HCC using SRB (sulforhodamine B) assays under normoxic and hypoxic conditions. Additionally, we analyzed the combined effects of CT-707 and sorafenib at varying doses using SRB assays under hypoxic conditions. Flow cytometry was employed to measure apoptosis rates following treatment with CT-707 and sorafenib in hypoxia. Western blotting was used to examine the expression levels of apoptosis-related proteins and to elucidate how CT-707 overcomes sorafenib resistance in hypoxia.

Results: Our findings indicate that intratumoral hypoxia, characteristic of advanced HCC, significantly contributes to sorafenib resistance. Importantly, CT-707, a novel multi-kinase inhibitor, sensitized hypoxic HCC cells to sorafenib. Further investigation revealed that CT-707 inhibited the nuclear translocation of Yes-Associated Protein (YAP), a mechanism implicated in hypoxia-induced sorafenib resistance in HCC.

Conclusions: This study supports the development of CT-707 as a promising therapeutic agent against HCC. Moreover, it proposes a potential strategy to overcome hypoxia-induced sorafenib resistance in HCC patients.