Disrupting DDB2-DNA Interaction by Lapatinib Enhances Chemotherapy Sensitivity

Area of Science:

• Molecular biology
• Cancer research
• Drug discovery

Background:

• Chemoresistance is a major challenge in cancer therapy.
• Damaged DNA-binding protein 2 (DDB2) is implicated in chemoresistance via DNA repair and apoptosis inhibition.
• Upregulation of DDB2 correlates with poor prognosis in several cancers.

Purpose of the Study:

• To investigate the role of DDB2 in chemoresistance.
• To identify novel therapeutic strategies targeting DDB2.
• To evaluate lapatinib as a DDB2 inhibitor and chemosensitizer.

Main Methods:

• Structure-based virtual screening and molecular dynamics simulations to identify DDB2 inhibitors.
• Cellular thermal shift assay and chromatin fractionation to confirm drug-target interaction.
• In vitro and ex vivo studies using cancer cell lines and patient-derived organoids to assess drug efficacy.

Main Results:

• Elevated DDB2 levels in breast, liver, cholangiocarcinoma, and lung cancers correlate with reduced patient survival.
• Lapatinib identified as a disruptor of the DDB2/DNA complex, reducing DDB2 chromatin association and promoting its degradation.
• Co-treatment with lapatinib and doxorubicin showed synergistic cytotoxicity in cancer models.

Conclusions:

• DDB2 is a critical mediator of chemoresistance.
• Lapatinib exhibits a novel mechanism of action by targeting DNA repair machinery.
• Repurposing lapatinib as a chemosensitizing agent offers a new strategy to overcome chemoresistance.