PARP Inhibitor Combination Therapy Boosts Antitumor Activity in NSCLC Models

Drug resistance remains a central obstacle in the treatment of non-small cell lung cancer (NSCLC) and other lung cancers, even as targeted therapies have improved outcomes for patients whose tumors are driven by mutations in EGFR, KRAS, or other oncogenes. Now, a preclinical study suggests that pairing the HER3-targeting antibody-drug conjugate HER3-DXd with the PARP inhibitor olaparib could offer a way to intensify DNA damage in tumor cells while also stimulating antitumor immune activity.

The study, “PARP inhibition enhances the antitumor activity of HER3-DXd in non-small cell lung cancer,” was published in Cell Reports Medicine. Researchers from Tampere University, the University of Helsinki, Harvard Medical School, and Dana-Farber Cancer Institute investigated whether HER3-DXd, also known as patritumab deruxtecan, could be made more effective through rational combination strategies involving modulators of the cell cycle and DNA damage response.

HER3 is expressed in many NSCLC tumors and has been associated with poor prognosis when overexpressed, making it an attractive therapeutic target. HER3-DXd is designed to bind HER3 on cancer cells and deliver a topoisomerase I inhibitor payload that damages DNA. Olaparib, meanwhile, blocks PARP-mediated DNA repair. The combination was intended to push cancer cells beyond their capacity to repair DNA damage.

The researchers screened HER3-DXd alongside drugs that affect cell-cycle regulation and DNA damage repair, identifying PARP inhibition as a strong synergistic partner. In NSCLC models carrying either EGFR or KRAS mutations, the HER3-DXd and olaparib combination was more effective than either agent alone. The dual treatment increased markers of DNA damage, induced apoptosis, and slowed tumor progression in vivo.

Those effects were not limited to direct tumor-cell killing. The combination also activated the cGAS-STING pathway, an innate immune signaling pathway that can be triggered by cytosolic DNA. In the study, this immune activation appeared to enhance natural killer cell-mediated tumor killing, suggesting that the regimen may have antibody-dependent immunomodulatory effects in addition to its DNA-damaging activity.

“A key finding was that the treatment combination was effective across multiple genetically distinct forms of lung cancer and was not dependent on any specific mutation. In fact, the HER3 protein could eventually serve as a biomarker for identifying patients who are likely to benefit from this type of treatment,” said Heidi Haikala, PhD, senior research fellow at Tampere University and assistant professor at the University of Helsinki.

The findings point to a possible strategy for patients whose tumors do not respond adequately to existing targeted therapies or develop resistance after treatment. Because HER3 is also present in other solid tumors, the authors suggested that the approach could have applications beyond NSCLC.

Still, the authors cautioned that the work remains preclinical. The study relied on a limited number of organoid lines and used immunocompromised mice for in vivo experiments, which may restrict how broadly the immune findings can be generalized. The researchers also noted that potential toxicities, including possible liver-related effects with prolonged combination treatment, will require more detailed evaluation before the regimen can move toward human trials.

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