Novel Therapeutic Strategy for Renal Cell Carcinoma: Niclosamide Enhances Sunitinib Efficacy via DNA Repair and Cell Cycle Pathways

Tyrosine kinase inhibitors (TKIs), such as sunitinib and sorafenib, are standard treatments for renal cell carcinoma (RCC). However, most patients treated with these drugs eventually develop drug resistance and relapse; therefore, new treatment options for RCC are urgently required. Recent studies have focused on combination therapies targeting distinct molecular pathways that may produce synergistic effects and help overcome drug resistance in RCC. Niclosamide, an anthelmintic agent, is effective against various cancers; however, its potential in combination with sunitinib for treating RCC has not been evaluated. In this study, we assessed the therapeutic efficacy of niclosamide in combination with sunitinib against RCC and explored the underlying molecular mechanisms. Niclosamide alone inhibited RCC cell proliferation, whereas its combination with sunitinib produced a synergistic anticancer effect, both in vitro and in vivo. RNA sequencing (RNA-seq) and bioinformatic analyses showed that niclosamide modulated critical pathways, including <i>BRIP1</i>- and <i>FANCA</i>-mediated DNA repair and <i>E2F2</i>-regulated cell cycle progression. These findings provide proof-of-concept that niclosamide enhances TKI efficacy through modulation of DNA repair and cell cycle pathways, supporting the rationale for DNA damage response (DDR)-targeted combination strategies in RCC.