Fruquintinib Potentiates the Radiosensitivity of Colorectal Cancer by Exacerbating DNA Damage

Objective Radiotherapy is pivotal for colorectal cancer (CRC) treatment, but radioresistance restricts its efficacy. Fruquintinib, a tyrosine kinase inhibitor, has anti-tumor activity, yet its role in enhancing CRC radiosensitivity and underlying mechanisms remain unclear. This study aimed to investigate these aspects in vitro and in vivo. Methods HCT-15 and SW620 CRC cells 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 (SER: 1.146–1.696), induced G0/G1 phase arrest, suppressed migration, and enhanced apoptosis. Western blotting showed FR-upregulated γH2A.X, which was abrogated by DNA-PKcs silencing. In xenografts, combined therapy significantly reduced tumor volume and weight without severe toxicity, and increased TUNEL-positive apoptotic cells. Conclusion Fruquintinib enhances CRC radiosensitivity in vitro and in vivo by inducing G0/G1 arrest, inhibiting migration, and promoting apoptosis via a DNA-PKcs-mediated DNA damage pathway. It holds promise as a radiosensitizer for CRC treatment.