Abstract 599: Oligomeric proanthocyanidins overcome Lenvatinib resistance by targeting ITGA3 and EGFR-AKT pathways in hepatocellular carcinoma

Background: Hepatocellular carcinoma (HCC) is the third most common cancer worldwide and is often diagnosed at an advanced stage, with chemotherapy often being the treatment of choice. Lenvatinib, a multi-targeted tyrosine kinase inhibitor, is widely used as a first-line therapy for advanced HCC following the REFLECT trial, demonstrating its non-inferiority to Sorafenib in overall survival. Additionally, combination therapies with immune checkpoint inhibitors or transarterial chemoembolization have shown promising results, with clinical studies indicating improved overall survival compared to monotherapies. However, frequent resistance to Lenvatinib significantly limits its clinical efficacy, necessitating novel strategies to address this challenge. Various pathways have been reported for the mechanisms of Lenvatinib resistance, including activation of EGFR, changes in the immune microenvironment, and activation of tumor stem cells. Oligomeric proanthocyanidins (OPCs), natural polyphenols with broad-spectrum anticancer properties, may enhance Lenvatinib’s efficacy by targeting these resistance pathways. This study aims to elucidate the mechanisms of Lenvatinib resistance and evaluate the potential of OPCs to overcome resistance in HCC. Methods: Lenvatinib-resistant Huh-7 and PLC-PRF-5 cell lines were generated through long-term exposure to increasing concentrations of Lenvatinib. We performed a series of cell culture experiments to evaluate the synergistic anticancer effect of the combination of Lenvatinib and OPCs in Lenvatinib-resistant cell lines. By performing genome-wide transcriptomic profiling, we identified specific growth-signaling pathways targeted by the combined treatment and validated these findings in cell lines. Results: The combination therapy of Lenvatinib and OPCs yielded promising results, significantly suppressing cell proliferation, invasion, and spheroid formation in Lenvatinib-resistant HCC cells. Transcriptomic analysis revealed that ITGA3 is a critical factor in Lenvatinib resistance, and its upregulation is associated with poor prognosis in HCC patients. Furthermore, high ITGA3 expression in resistant cells was found to promote activation of the EGFR-AKT pathway and enhance resistance to anoikis, contributing to Lenvatinib resistance. Molecular analyses demonstrated that this combination therapy effectively suppresses the ITGA3, EGFR-AKT pathway, thereby overcoming Lenvatinib resistance and supporting the promising results of this treatment. Conclusion: This study identifies OPCs as a promising therapeutic agent for overcoming Lenvatinib resistance by targeting ITGA3 and the EGFR-AKT pathways. The results emphasize the potential benefits of combining OPCs with Lenvatinib to enhance therapeutic efficacy and improve outcomes in Lenvatinib-resistant HCC. Citation Format: Takayuki Noma, Yuan Li, Yuma Wada, Katsuki Miyazaki, Yuji Morine, Mitsuo Shimada, Ajay Goel. Oligomeric proanthocyanidins overcome Lenvatinib resistance by targeting ITGA3 and EGFR-AKT pathways in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 599.