Lung cancer models built from patient-derived cells have revealed a potentially powerful way to overcome treatment resistance: pairing the antibody-drug conjugate patritumab deruxtecan, also known as HER3-DXd, with the DNA-repair inhibitor olaparib. In a new preclinical study, researchers from Tampere University, the University of Helsinki, Harvard University and the Dana-Farber Cancer Institute found that the combination produced substantially stronger antitumour effects than either treatment alone. The therapy damaged cancer-cell DNA beyond the point of repair, activated innate immune signalling and improved the ability of natural killer cells to eliminate malignant cells. The findings could help establish a rationale for clinical trials involving patients with non-small cell lung cancer, including tumours driven by EGFR or KRAS mutations.
Lung cancer remains the world’s most commonly diagnosed cancer and its leading cause of cancer-related mortality. Although declining smoking rates have reduced incidence among men in many countries, lung cancer is increasing among younger women who have never smoked. Non-small cell lung cancer accounts for most cases and is frequently associated with genetic alterations that continuously stimulate cellular growth. Mutations in the epidermal growth factor receptor, or EGFR, can keep growth-promoting signals switched on, while alterations in KRAS can disrupt a central molecular relay that transmits those signals inside the cell. Targeted inhibitors directed against these pathways have transformed treatment for many patients, yet resistance commonly emerges as tumours adapt, acquire additional mutations or activate alternative survival mechanisms.
The new approach focuses on HER3, a member of the epidermal growth factor receptor family that is present on the surface of most non-small cell lung cancers. HER3-DXd is an antibody-drug conjugate designed to exploit this molecular feature. Its antibody component binds to HER3 on cancer cells and is taken into the cell, where the attached drug is released. The payload belongs to the topoisomerase I inhibitor class and interferes with the process by which DNA is unwound and copied. This creates DNA lesions that can become particularly toxic when a cancer cell is dividing. Because HER3 is broadly expressed across genetically different lung tumours, the strategy may be less dependent on a single oncogenic mutation than conventional targeted therapies.
Olaparib attacks a different vulnerability. It inhibits PARP proteins, which help detect and repair certain forms of DNA damage, including single-strand breaks. When PARP activity is blocked, these lesions can persist and become more dangerous during DNA replication, eventually developing into double-strand breaks. Healthy cells often possess several overlapping repair systems, but tumour cells may already be operating under considerable genomic stress or may carry defects in DNA-repair pathways. Combining olaparib with HER3-DXd therefore creates a form of therapeutic pressure in which the antibody-drug conjugate generates extensive damage while the PARP inhibitor prevents the cancer cell from resolving it. The result is an accumulation of irreparable lesions and activation of programmed cell death, or apoptosis.
Experiments described in the study showed that the combination was significantly more effective than either HER3-DXd or olaparib used separately. The researchers observed increased markers of DNA damage and a greater loss of cancer-cell viability in models of non-small cell lung cancer. Importantly, the effect was detected in models carrying both EGFR and KRAS mutations, two genetically distinct settings that often respond differently to treatment. This broad activity suggests that the combination may work through a biological vulnerability shared by many lung cancers rather than relying exclusively on the presence of one particular driver mutation. The findings also raise the possibility that tumours that have become resistant to standard EGFR-directed therapies could remain susceptible to a treatment based on HER3 expression and DNA-repair disruption.
The researchers tested the therapy in more complex experimental systems as well as in cultured cells. A cancer-on-a-chip model constructed from a patient’s own cancer cells reproduced features of a tumour together with its surrounding vasculature, allowing the investigators to examine treatment responses under laboratory conditions that more closely resemble human disease. Such models can capture interactions between tumour cells, blood-vessel-like structures and therapeutic agents that are difficult to reproduce in conventional two-dimensional cultures. In animal studies, the combined treatment slowed tumour growth and extended survival compared with single-agent therapy. These results strengthen the evidence that the interaction between HER3-DXd and olaparib is not limited to an artificial laboratory setting.
The treatment also appeared to stimulate an immune response against the tumour. One important mechanism involved the cGAS-STING pathway, a surveillance system that detects abnormal DNA in the cell. When damaged or misplaced DNA accumulates in the cytoplasm, the enzyme cGAS can generate cyclic GMP-AMP, which activates the adaptor protein STING. This signalling cascade induces inflammatory mediators and interferon-related responses that alert the innate immune system to cellular danger. By increasing DNA damage, the drug combination may therefore make tumour cells more visible to immune defences. In the study, this response was accompanied by improved activity of natural killer cells, immune cells that can recognise and destroy stressed or abnormal cells without requiring the same antigen-specific priming as conventional T-cell responses.
This dual action is significant because successful cancer therapy often depends on more than direct tumour-cell killing. A treatment that damages cancer cells but leaves behind a microenvironment capable of suppressing immunity may produce only a temporary response. By contrast, the HER3-DXd and olaparib combination appears to link intracellular DNA damage with external immune activation. The damaged tumour may release signals that encourage inflammation, while natural killer cells gain a greater capacity to attack malignant targets. Whether this immune effect will be equally strong in patients remains unknown, since human tumours contain diverse immune populations and often develop mechanisms that block immune surveillance. Nevertheless, the preclinical observations provide a mechanistic basis for investigating the combination alongside other immunomodulatory strategies.
The researchers suggest that HER3 itself could eventually serve as a biomarker for selecting patients most likely to benefit. Unlike a mutation-specific marker, HER3 expression could identify a wider group of patients whose tumours possess the molecular entry point required for HER3-DXd. However, expression alone may not fully predict response. The amount of HER3 on the cell surface, the efficiency with which the antibody-drug conjugate is internalised, the condition of the tumour’s DNA-repair machinery and the composition of the immune microenvironment could all influence treatment outcomes. Clinical studies will need to determine the appropriate doses, establish whether the combination produces manageable levels of toxicity and clarify how HER3 abundance, EGFR or KRAS status and previous treatment history affect response.
The study’s findings may have implications beyond lung cancer. HER3 is frequently detected in other solid tumours, including several cancers in which resistance to targeted therapy remains a major clinical challenge. If the same relationship between HER3-directed drug delivery, PARP inhibition and immune activation is observed in patients, the strategy could potentially be adapted to additional tumour types. At present, however, the evidence remains preclinical, and results from cell cultures, organ-like models and laboratory animals cannot guarantee benefit in humans. The work provides a strong foundation for clinical testing, but future trials will be essential to determine whether this precisely engineered combination can translate its promise into longer, more durable responses for people with treatment-resistant cancer.
Subject of Research: A preclinical combination therapy using HER3-DXd and olaparib to treat non-small cell lung cancer.
Article Title: PARP inhibition enhances the antitumor activity of HER3-DXd in non-small cell lung cancer
News Publication Date: 21-Aug-2026
Web References: https://doi.org/10.1016/j.xcrm.2026.103002
References: Cell Reports Medicine, DOI: 10.1016/j.xcrm.2026.103002
Image Credits: Linh Lin and Bassel Alsaed
Keywords: Lung cancer, non-small cell lung cancer, HER3-DXd, patritumab deruxtecan, olaparib, PARP inhibition, DNA damage, EGFR, KRAS, cGAS-STING, natural killer cells, cancer immunology, targeted therapy, drug resistance, cancer-on-a-chip model
