Abstract 4736: Evaluate the potential sensitization effect and underlying mechanism of lenvatinib on cisplatin resistance oral squamous cell carcinoma

Abstract Oral squamous cell carcinoma (OSCC) is a prevalent form of cancer that develops in the oral cavity, globally recognized as the eighth most commonly diagnosed cancer. Despite the application of standard surgical techniques or concurrent chemoradiotherapy, the prognosis for OSCC patients remains unsatisfactory. Initially, cisplatin, the primary and most frequently used chemotherapy agent for treating OSCC, demonstrates effectiveness in therapy. Nonetheless, chemoresistance frequently arises, leading to treatment failure, and this is intricately associated with the activation of hypoxia-inducible factor 1α (HIF-1α) signaling. Recent research has brought to light heightened levels of HIF-1α-mediated vascular endothelial growth factor (VEGF) and BCL-2 in OSCC tumor sites, which play crucial roles in regulating angiogenesis and anti-apoptotic processes within cancer cells. Additionally, interventions aimed at targeting anti-apoptotic molecules or augmenting the expression of pro-apoptotic molecules may represent promising strategies to overcome chemoresistance in OSCC. Therefore, HIF-1α/VEGF/BCL-2 axis could be considered a potential target for the development of chemopreventive and chemotherapeutic strategies for OSCC. Lenvatinib is a targeted multi-kinase inhibitor that can inhibit tumor growth and angiogenesis by blocking the activation of vascular endothelial growth factor receptor (VEGFR) 1-3, fibroblast growth factor receptor (FGFR) 1-4, platelet-derived growth factor receptor (PDGFR) α, as well as the proto-oncogenes RET and KIT. However, whether lenvatinib may sensitizes OSCC to cisplatin remains unclear. In our study, we used the MTT assay to prove the cytotoxicity of OSCC cells (SAS and MOC1 cells) was induced by cisplatin and lenvatinib. We employed flow cytometry to verify that the combination of lenvatinib and cisplatin can indeed trigger both extrinsic and intrinsic apoptotic pathways in OSCC cells. Furthermore, our demonstration revealed that the induction of apoptosis pathways by the combination of lenvatinib and cisplatin is associated with mitochondrial-dependent apoptosis and death receptor-dependent apoptosis. Then, transwell invasion and migration assay results proved the inhibition effect of lenvatinib combined with cisplatin in SAS and MOC1 cells. Furthermore, we indicated that the combination of lenvatinib and cisplatin can effectively inhibit angiogenesis and anti-apoptotic mechanisms mediated by the HIF-1α/VEGF/BCL-2 axis in OSCC cells. In summary, our results demonstrate that the combined treatment with lenvatinib and cisplatin enhances the response of OSCC cells under hypoxic conditions. Additionally, it aims to mitigate the negative impact of hypoxia on cisplatin's therapeutic effectiveness and increase the sensitivity of OSCC cells to cisplatin. Citation Format: Ying-Tzu Chen, Yan-Ting Tsai, Fei-Ting Hsu, Hsi-Feng Tu. Evaluate the potential sensitization effect and underlying mechanism of lenvatinib on cisplatin resistance oral squamous cell carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4736.