Disrupting DDB2-DNA Interaction by Lapatinib Enhances Chemotherapy Sensitivity.

Chemoresistance remains an obstacle to effective cancer therapy across multiple tumor types. Damaged DNA-binding protein 2 (DDB2), a key component of the nucleotide excision repair (NER) pathway, contributes to chemoresistance by enhancing DNA repair and inhibiting apoptosis. Although the role of DDB2 in tumor progression is context-dependent, its upregulation has been associated with poor prognosis in various malignancies. In this study, elevated DDB2 levels found in breast, liver, cholangiocarcinoma, and lung cancers correlated with reduced patient survival. DDB2 confers resistance to chemotherapeutic agents. Through structure-based virtual screening and molecular dynamics simulations, lapatinib, an FDA-approved EGFR/HER2 inhibitor, was identified as a compound capable of disrupting the DDB2/DNA complex, which was confirmed by the cellular thermal shift assay and chromatin fractionation. Mechanistically, lapatinib binds to the DNA-binding region of DDB2, thereby reducing its chromatin association and promoting proteasomal degradation. Co-treatment with lapatinib and doxorubicin exhibited synergistic cytotoxicity in both cancer cell lines and patient-derived organoids. These findings reveal a previously unrecognized role for lapatinib in targeting DNA repair machinery, supporting its repurposing as a chemosensitizing agent. Our study highlights DDB2 as a critical mediator of chemoresistance and proposes disruption of DDB2-dependent DNA repair as a novel strategy for chemosensitization.