PARP inhibition enhances the antitumor activity of HER3-DXd in non-small cell lung cancer.

Lung cancer, a leading cause of cancer-related mortality, is often driven by mutations in the key oncogenes epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma virus (KRAS). Despite advancements of targeted therapies such as tyrosine kinase inhibitors, resistance remains a significant hurdle. Overexpression of HER3, associated with poor prognosis in non-small cell lung cancer (NSCLC), presents an alternative therapeutic target. In this study, we investigate the efficacy of the HER3-targeting antibody-drug conjugate HER3-DXd and its synergistic potential when combined with cell cycle and DNA damage response modulators. A significant synergy is observed with PARP inhibitors, effective in both EGFR- and KRAS-mutated NSCLC models. This combination markedly enhances DNA damage, induces apoptosis, and slows down in vivo tumor progression. Notably, this regimen also triggers antibody-dependent immunomodulatory effects through cGAS-STING pathway activation, potentiating innate immune cells for tumor killing. Our findings suggest that combining HER3-DXd with PARP inhibitors offers a promising therapeutic approach, effectively targeting diverse NSCLC subtypes.