Abstract:
Hepatocellular Carcinoma (HCC), a primary type of liver cancer, remains one of the deadliest malignancies worldwide. Despite decades of targeted therapy advancements, the currently approved medications for advanced HCC provide patients with limited clinical benefits. One major obstacle to treatment is a lack of effective molecular-targeted therapies. Here we identified EPHA2 as a novel oncotarget that promotes HCC initiation and progression. We found that high EPHA2 signaling and expression is observed in over 30% of HCC patient samples and is associated with worse clinical outcomes. Loss of EphA2 suppressed the initiation and growth of HCC both in vitro and in vivo. Furthermore, CRISPR/CAS9 mediated EphA2 inhibition significantly delayed tumor development in a genetically engineered murine model of HCC. Mechanistically, we discovered that targeting EphA2 suppressed both AKT and JAK1/STAT3 signaling in HCC. We also demonstrated that treatment with a small molecule inhibitor of EPHA2, ALW-II-41-27, suppressed HCC progression in mice. In summary, our results suggest EphA2 as a promising therapeutic target for HCC.
