WILMINGTON, DE — A new study from ChristianaCare’s Gene Editing Institute shows that disabling a single gene with CRISPR technology can restore chemotherapy sensitivity in lung cancer, a development researchers say could reshape treatment strategies for some of the toughest tumor types. The findings were published in Molecular Therapy Oncology on Nov. 13.
The research centers on NRF2, a transcription factor long associated with chemotherapy resistance. When overactive, NRF2 enables cancer cells to survive the oxidative stress created by standard drugs, reducing treatment effectiveness. For more than a decade, the Gene Editing Institute has investigated NRF2’s role in solid tumors, and the latest results build directly on that work.
“This is compelling evidence at every stage of research,” said lead author Kelly Banas, Ph.D., associate director of research at the Gene Editing Institute. “It’s a strong foundation for taking the next step toward clinical trials.”
The study focused on lung squamous cell carcinoma, an aggressive form of non-small cell lung cancer that represents up to 30% of annual cases. Researchers used CRISPR/Cas9 to target a tumor-specific mutation, R34G, in the NRF2 gene. By knocking out NRF2 in engineered lung cancer cells, they restored responsiveness to chemotherapy agents such as carboplatin and paclitaxel.
In animal models, tumors treated directly with the CRISPR therapy grew more slowly and responded better to standard drugs. One of the most significant findings: achieving gene edits in just 20% to 40% of cancer cells was enough to improve treatment response, a potentially important threshold for future clinical use where whole-tumor editing is unlikely.
The team delivered CRISPR edits via lipid nanoparticles — a non-viral method known for high efficiency and low off-target risk. Sequencing confirmed highly specific edits to the mutated NRF2 gene with minimal unintended changes elsewhere in the genome.
“This work brings transformational change to how we think about treating resistant cancers,” said senior author Eric Kmiec, Ph.D., executive director of the Gene Editing Institute. “Instead of developing entirely new drugs, we are using gene editing to make existing ones effective again.”
Although the study focused on lung cancer, the implications run much farther. NRF2 overactivation drives treatment resistance in multiple solid tumors, including liver, esophageal, and head and neck cancers. The researchers say a CRISPR-based strategy aimed at NRF2 could help re-sensitize a wide spectrum of resistant tumors to chemotherapy.
For patients, the approach may one day allow for lower chemotherapy doses and fewer toxic side effects — a particularly meaningful advance for individuals whose options are limited once resistance develops.
“This is a significant step toward overcoming one of the biggest challenges in cancer therapy,” Banas said. “We’re hopeful this strategy will translate into healthier patients who respond better and stay responsive longer.”
The full study is available through Molecular Therapy Oncology.
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