Fruquintinib potentiates the radiosensitivity of colorectal cancer by exacerbating DNA damage

OBJECTIVE: To investigate the radiosensitizing effect of fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, on colorectal cancer (CRC), and to determine whether this effect is mediated not only through anti-angiogenic activity but also via direct cellular mechanisms involving the modulation of DNA damage repair, while further assessing the synergistic inhibition of the combined treatment on malignant tumor cell phenotypes. METHODS: CRC cell lines of primary (HCT-15) and metastatic (SW620) origin were treated with fruquintinib alone or combined with X-ray irradiation. CCK-8, colony formation, flow cytometry (Annexin V/PI staining), wound-healing assay, and Western blotting were used to assess cell viability, radiosensitivity, apoptosis, migration, and DNA damage. A nude mouse HCT-15 xenograft model was established to verify in vivo efficacy. RESULTS: Fruquintinib inhibited CRC cell viability dose- and time-dependently. Combined with irradiation, it significantly reduced cell survival, induced G0/G1 phase arrest, suppressed cell migration, and enhanced apoptosis. Western blotting showed fruquintinib administered concomitant with irradiation (FR)-upregulated γH2A.X expression, which was abrogated by DNA-PKcs silencing. In xenograft tumors, combined therapy significantly reduced tumor volume and weight without severe toxicity, and increased the number of TUNEL-positive cells. CONCLUSION: Fruquintinib acts as an effective radiosensitizer in colorectal cancer. Its mechanism involves the disruption of DNA damage repair in tumor cells. This study provides new evidence supporting the clinical combination of fruquintinib with radiotherapy.