Summary
A critical challenge in hepatocellular carcinoma (HCC) treatment is the development of resistance against sorafenib, a valued therapy option for advanced liver cancer. Despite sorafenib’s initial effectiveness, many patients eventually develop resistance, limiting its long-term benefits. In an attempt to tackle this problem, an RNA interference (RNAi) screening approach in mouse models of liver cancer was employed to identify genetic factors that contribute to this resistance.
The initial findings revealed that the MAPK14 gene, which encodes the p38α kinase, plays a crucial role in the development of resistance to sorafenib. By silencing MAPK14 using RNAi or pharmacologically inhibiting p38α, we demonstrated an enhanced response to sorafenib, suggesting that targeting this pathway could restore or improve the drug’s efficacy.
This discovery was judged to have a high translational potential by opening up the possibility of combining sorafenib with p38α inhibitors as a potential therapeutic strategy to overcome resistance in HCC patients.
The first-in-class p38 inhibitor Skepinone-L (SKL) was therefore tested in different animal models and revealed a promising response in the combination of sorafenib in HCC. SKL was chosen for further investigation and was preclinically developed via academic funding sources exclusively. The candidate showed favorable profiles in preclinical toxicity studies and demonstrated a good tolerability in a named patient use setting.
The first-in-human clinical trial is currently under preparation within the network of the National Center for Tumor Diseases (NCT) and will be starting soon in a multicentric setup within the NCT.
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