Niclosamide synergizes with sunitinib against renal cell carcinoma via regulation of 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 effectice 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 this combination in RCC. 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 BRIP1- and FANCA-mediated DNA repair and E2F2-regulated cell cycle progression. These findings suggest that niclosamide may be repurposed as an anticancer agent to enhance the efficacy of targeted therapies for RCC, supporting its potential for clinical application as part of a combination treatment strategy.