Study in Molecular Therapy Oncology shows gene editing restores drug sensitivity by targeting NRF2, with potential across multiple tumor types

(WILMINGTON, Del. – November 17, 2025)

In a major step forward for cancer care, researchers at ChristianaCare’s Gene Editing Institute have shown that disabling the NRF2 gene with CRISPR technology can reverse chemotherapy resistance in lung cancer. The approach restores drug sensitivity and slows tumor growth. The findings were published Nov. 13, 2025 in the online edition of Molecular Therapy Oncology.

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This breakthrough stems from more than a decade of research by the Gene Editing Institute into the NRF2 gene, a known driver of treatment resistance. The results were consistent across multiple in vitro studies using human lung cancer cell lines and in vivo animal models.

“We’ve seen compelling evidence at every stage of research,” said Kelly Banas, Ph.D., lead author of the study and associate director of research at the Gene Editing Institute. “It’s a strong foundation for taking the next step toward clinical trials.”

Potential Beyond Lung Cancer
The study focused on lung squamous cell carcinoma, an aggressive and common form of non-small cell lung cancer (NSCLC) that accounts for 20% to 30% of all lung cancer cases, according to the American Cancer Society. It’s estimated that over 190,000 people in the U.S. will be diagnosed in 2025.

While the research centered on this cancer type, the implications are broader. Overactive NRF2 contributes to chemotherapy resistance in several solid tumors, including liver, esophageal and head and neck cancers. The results suggest a CRISPR-based strategy targeting NRF2 could help resensitize a wide range of treatment-resistant tumors to standard chemotherapy.

“This is a significant step toward overcoming one of the biggest challenges in cancer therapy — drug resistance,” Banas said. “By targeting a key transcription factor that drives resistance, we’ve shown that gene editing can re-sensitize tumors to standard treatment. We’re hopeful that in clinical trials and beyond, this is what will allow chemotherapy to improve outcomes for patients and could enable them to remain healthier during the entirety of their treatment regimen.”

Targeting a Master Switch for Resistance
The research zeroed in on a tumor-specific mutation, R34G, in the NRF2 gene, which acts as a master regulator of cellular stress responses. When overactive, NRF2 helps cancer cells withstand chemotherapy.

Using CRISPR/Cas9, the team engineered lung cancer cells with the R34G mutation and successfully knocked out NRF2. This restored sensitivity to chemotherapy drugs such as carboplatin and paclitaxel. In animal models, tumors directly treated with CRISPR to knockout NRF2 grew more slowly and responded better to treatment.

“This work brings transformational change to how we think about treating resistant cancers,” said Eric Kmiec, Ph.D., senior author of the study and executive director of the Gene Editing Institute. “Instead of developing entirely new drugs, we are using gene editing to make existing ones effective again.”

Editing Reaches Threshold Levels
One of the most promising discoveries was that disrupting NRF2 in just 20% to 40% of tumor cells, was enough to improve the response to chemotherapy and shrink tumors. This insight is particularly relevant for clinical use, where editing every cancer cell may not be feasible.

To test therapy in mice, the researchers used lipid nanoparticles (LNPs), a non-viral method with high efficiency and low risk of unintended, off-target effects. Sequencing confirmed that the edits were highly specific to the mutated NRF2 gene, with minimal unintended changes elsewhere in the genome.

“The power of this CRISPR therapy lies in its precision. It’s like an arrow that hits only the bullseye,” said Banas. “This level of specificity with minimal unanticipated genomic side effects offers real hope for the cancer patients who could one day receive this treatment.”

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About ChristianaCare

Headquartered in Wilmington, Delaware, ChristianaCare is one of the country’s most dynamic health care organizations, centered on improving health outcomes, and innovating to make high-quality care more accessible, equitable and affordable. ChristianaCare includes an extensive network of primary care and outpatient services, home health care, urgent care centers, four hospitals (1,440 beds), a freestanding emergency department, a Level I trauma center and a Level III neonatal intensive care unit, a comprehensive stroke center and regional centers of excellence in heart and vascular care, cancer care and women’s health. It also includes the pioneering Gene Editing Institute and a 10-bed neighborhood hospital in West Grove, PA.

ChristianaCare is nationally recognized as a great place to work. ChristianaCare is rated by Newsweek as one of the World’s Best Hospitals and is continually ranked among the best in the U.S. in national quality and safety ratings. ChristianaCare is a nonprofit teaching health system with more than 260 residents and fellows. With its groundbreaking Center for Virtual Health and a focus on population health and value-based care, ChristianaCare is shaping the future of health care.

About the ChristianaCare Gene Editing Institute

The Gene Editing Institute at ChristianaCare is a worldwide leader in CRISPR gene editing technology. As the only institute of its kind based within a community health care system, the Gene Editing Institute has a unique opportunity to take a patient-first approach in all its research by working side by side with oncologists and other medical experts to improve the lives of people with cancer and inherited diseases. Since 2015, its researchers have led several ground-breaking firsts in the field that will help bring treatments to patients quickly and safely. They recently discovered that disabling a lung cancer gene called NRF2 using CRISPR gene editing allows chemotherapy work better to target cancer cells. Lung cancer resistance to chemotherapy has long been elusive. The Gene Editing Institute, working with its spin out company CorriXR Therapeutics, is close to approval from the FDA to start clinical trials in humans. In addition to scientific breakthroughs, The Gene Editing Institute is preparing the next generation of gene editing scientists through its on-site Learning Lab and immersive CRISPR In A Box™ teaching toolkit reaching more than 1,000 students across multiple states.

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