Researchers at ChristianaCare’s Gene Editing Institute report that disabling the NRF2 gene with CRISPR restored chemotherapy sensitivity in models of squamous non‑small cell lung cancer and slowed tumor growth, with benefits seen even when only a fraction of tumor cells were edited. The work was published online November 13, 2025 in Molecular Therapy Oncology.
Scientists at ChristianaCare’s Gene Editing Institute say CRISPR-directed disruption of NRF2, a master stress‑response regulator, revived chemotherapy response in drug‑resistant lung cancer models and curbed tumor growth. The preclinical findings appeared November 13, 2025 in Molecular Therapy Oncology and reflect more than a decade of the institute’s research into NRF2’s role in treatment resistance, according to the group.
The team focused on lung squamous cell carcinoma, a form of non‑small cell lung cancer (NSCLC) that accounts for roughly a quarter of NSCLC cases. The American Cancer Society projects about 226,650 new lung and bronchus cancer diagnoses in the United States in 2025, underscoring the potential impact of strategies that restore sensitivity to standard drugs such as carboplatin and paclitaxel.
Researchers engineered lung cancer cells to carry a tumor‑specific NRF2 mutation (R34G) and then used CRISPR/Cas9 to knock out NRF2. In cell studies, the edits re‑sensitized tumors to chemotherapy. In mouse models, directly delivering the CRISPR treatment to tumors slowed growth and enhanced the effectiveness of chemotherapy, the institute reports.
“We’ve seen 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.”
A notable finding, the researchers said, was that editing only about 20% to 40% of tumor cells improved response and reduced tumor size—an important consideration because reaching every cell in a solid tumor is unlikely in practice. In the mouse studies, CRISPR components were packaged in lipid nanoparticles, a non‑viral delivery method the team says yielded highly targeted edits with minimal off‑target effects.
“This work brings transformational change to how we think about treating resistant cancers,” said senior author Eric Kmiec, Ph.D., the institute’s executive director. “Instead of developing entirely new drugs, we are using gene editing to make existing ones effective again.”
Because NRF2 overactivation is implicated in therapy resistance beyond lung cancer, including in head and neck, esophageal and liver tumors, the authors say the same approach could have broader applications. The results remain preclinical; the institute says additional safety and regulatory studies are underway to prepare for potential human trials.
