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Anti-Cancer Effects of YAP Inhibitor (CA3) in Combination with Sorafenib against Hepatocellular Carcinoma (HCC) in
Sojung Han1,2, Ji Yeon Lim3, Kyungjoo Cho3
1Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea.
Purpose:
To assess the expression levels of YAP and TAZ in patient-derived HCC tissue and identify the effects of YAP/TAZ inhibition depending on the baseline YAP/TAZ expression when combined with sorafenib using a patient-derived multicellular tumor spheroid (MCTS) model.
Methods:
Primary HCC cell lines were established from patient-derived tissue. Six patient-derived HCC cell lines were selected according to YAP/TAZ expression on Western blot: high, medium, low. Then, MCTS was generated by mixing patient-derived HCC cells and stroma cells (LX2, WI38, and HUVECs) and YAP/TAZ expression was assessed using Western blot. Cell viability of MCTS upon 48 h of drug treatment (sorafenib, sorafenib with CA3 0.1 µM, and CA3 (novel YAP1 inhibitor)) was analyzed.
Results:
Out of six patient-derived HCC cell lines, cell lines with high YAP/TAZ expression at the MCTS level responded more sensitively to the combination therapy (Sorafenib + CA3 0.1 μM) despite the potent cytotoxic effect of CA3 exhibited in all of the patient-derived HCCs.
Conclusion:
Targeting YAP/TAZ inhibition using the novel YAP1 inhibitor CA3 could be a promising therapeutic strategy to enhance sensitivity to sorafenib especially in HCCs with high YAP/TAZ expression in MCTS.
Insights
Targeting YAP/TAZ in hepatocellular carcinoma (HCC) with high expression may enhance sorafenib treatment effectiveness. A novel YAP1 inhibitor, CA3, combined with sorafenib showed increased sensitivity in patient-derived models.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Hepatocellular carcinoma (HCC) remains a significant global health challenge.
- Yeast and Actin-binding protein (YAP) and Transcriptional Coactivator with PDZ-binding motif (TAZ) are key regulators in cancer progression.
- Identifying novel therapeutic targets and combination strategies is crucial for improving HCC treatment outcomes.
Purpose of the Study:
- To evaluate YAP and TAZ expression in patient-derived HCC tissues.
- To investigate the efficacy of YAP/TAZ inhibition combined with sorafenib in a patient-derived multicellular tumor spheroid (MCTS) model.
- To determine if baseline YAP/TAZ expression influences treatment response.
Main Methods:
- Established primary HCC cell lines from patient tissues.
- Categorized cell lines into high, medium, and low YAP/TAZ expressors via Western blot.
- Developed MCTS models using HCC cells and various stroma cells (LX2, WI38, HUVECs).
- Assessed MCTS viability after treatment with sorafenib, CA3 (YAP1 inhibitor), and their combination.
Main Results:
- HCC cell lines with high YAP/TAZ expression in MCTS models demonstrated increased sensitivity to the combination of sorafenib and CA3 (0.1 μM).
- The novel YAP1 inhibitor CA3 exhibited potent cytotoxic effects across all tested patient-derived HCCs.
- Baseline YAP/TAZ expression levels in MCTS correlated with response to combination therapy.
Conclusions:
- Inhibition of YAP/TAZ using the novel YAP1 inhibitor CA3 presents a promising strategy.
- This approach can potentially enhance sorafenib sensitivity, particularly in HCCs with high YAP/TAZ expression.
- The MCTS model provides a valuable platform for evaluating targeted therapies in HCC.
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