Abstract 695: Enhancing radiotherapy with lenvatinib by targeting the CXCL13/CXCR5/NF-ΚB axis
Authors: Liao Tsai-Lan , Chiang I-Tsang , Huang Bo-Han , Hsu Fei-Ting , Chan Ming-Hsien 
Published: March 2024

Abstract
Lung cancer is the leading cause of cancer death worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all lung cancers. At the time of diagnosis, it is often already advanced or metastatic, resulting in poor treatment outcomes. Treatment of NSCLC mainly relies on surgery, radiation and chemotherapy, but the survival rate has not increased significantly in the past decade. Therefore, finding appropriate treatment methods is necessary and crucial. Radiotherapy (RT) is a frequently employed approach for tumor treatment and serves as the primary local treatment for NSCLC. However, it often results in a poor prognosis and severe side effects when administered at high-dose irradiation. Existing literature suggests that RT may trigger the expression of nuclear factor kappa B (NF-ΚB), potentially compromising its therapeutic efficacy. Consequently, the question remains: Can targeting NF-ΚB signaling enhance the sensitivity of RT in NSCLC Furthermore, studies have indicated that elevated levels of CXCR5 in NSCLC contribute to tumor growth. CXCR5 is situated upstream of the NF-ΚB pathway. As a result, it becomes imperative and indispensable to develop strategies targeting the CXCL13/CXCR5/NF-ΚB signaling axis to counteract NSCLC growth. Lenvatinib is a multi-kinase inhibitor targeted drug. It has been proven to inhibit VEGFR1-3, FGFR1-4 and PDGFR, inhibiting tumor growth. Lenvatinib has received clinical approval from the US FDA for the treatment of advanced hepatocellular carcinoma (HCC) and has been shown to inhibit NF-ΚB expression in HCC. However, the potential radiation-sensitizing mechanism of Lenvatinib in lung cancer remains unexplored. This study is dedicated to investigating the effects and molecular mechanisms of combining Lenvatinib with radiotherapy in NSCLC. Our results suggest that lenvatinib may enhance the sensitivity of NSCLC to RT. Furthermore, evidence from both the intrinsic and extrinsic apoptosis pathways (Caspase-3/Caspase-8/Caspase-9) and TUNEL experiments supports the idea that the combined treatment of lenvatinib with RT induces a more pronounced apoptotic response compared to individual treatments. Additionally, silencing CXCR5 in NSCLC also appears to enhance its responsiveness to RT. In our western blot (p-ATM, p-CHK2), flow cytometry (p-ATM), we showed that the combination of lenvatinib and RT may effective induce DNA damage. Our in vivo data demonstrates that the combination of Lenvatinib and RT exhibits superior tumor growth inhibition. Immunohistochemistry (IHC) staining of tumor tissue also revealed an upregulation of apoptosis-related proteins and the downregulation of CXCL13/CXCR5/NF-ΚB related proteins. In conclusion, our findings suggest that Lenvatinib can serve as a radiosensitizer, enhancing the sensitivity of NSCLC patients to radiotherapy by targeting the CXCL13/CXCR5/NF-ΚB signaling pathway.
Citation Format: Tsai-Lan Liao, I-Tsang Chiang, Bo-Han Huang, Fei-Ting Hsu, Ming-Hsien Chan. Enhancing radiotherapy with lenvatinib by targeting the CXCL13/CXCR5/NF-ΚB axis [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(6_Suppl):Abstract nr 695.