New combination therapy improves outcomes in preclinical lung cancer studies
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Researchers have discovered that pairing the antibody-drug conjugate patritumab deruxtecan with the DNA-repair inhibitor olaparib creates a potent combination therapy against non-small cell lung cancer in preclinical models.
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.
