19P - KSR1 as a therapeutic target for hepatocellular carcinoma with activated RAS-RAF-MEK-ERK signaling pathway

Background

Hepatocellular carcinoma (HCC) ranks as the 6th most commonly diagnosed cancer worldwide and is the 3rd leading cause of cancer-related deaths. More than 50% of patients with HCC exhibit abnormal activation of the RAS-RAF-MEK-ERK signaling pathway in their tumors. Kinase Suppressor of Ras 1 (KSR1) is a pivotal scaffold protein for the RAS-RAF-MEK-ERK signaling pathway and facilitates the assembly and activation of key signaling components within the pathway. Here, we investigated the oncogenic role of KSR1 in hepatic tumorigenesis and therapeutic effects of targeting KSR1 on HCC induced by activated RAS-RAF-MEK-ERK signaling.

Methods

Transgenic mouse model for HCC was created via hydrodynamic tail veil injection (HTVI). Livers were harvested and examined for the presence of tumors through gross examination. Tumor tissues were then formalin-fixed and further processed for immunohistochemical analysis. To suppress the activity of KSR1 in HCC induced in the murine model, we employed two approaches: the expression of short hairpin RNA downregulating KSR1 (shKSR1) in the tumor, and the administration of mice with APS-2-79, a pharmacological inhibitor of KSR.

Results

Tumors were observed in livers expressing both KSR1 and shRNA down-regulating P53 (shP53), while the expression of KSR1 or shP53 alone failed to induce tumors. Expression of KSR1 led to elevated levels of MEK and ERK phosphorylation, suggesting that KSR1 promotes tumorigenesis in the liver by activating the RAS-RAF-MEK-ERK signaling pathway. Inhibition of KSR1 in tumors induced by activated RAS (HRAS^G12V) led to a significant reduction in tumorigenesis in the mouse models. Additionally, the administration of APS-2-79 to mice harboring RAF-induced HCC led to an increase in overall survival.

Conclusions

Our findings indicate that targeting KSR1 is a promising strategy for the treatment of HCC driven by activated RAS-RAF-MEK-ERK signaling.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

National Research Foundation of Korea.

Disclosure

All authors have declared no conflicts of interest.