Researchers at ChristianaCare's Gene Editing Institute have achieved a significant breakthrough in cancer treatment by demonstrating that CRISPR technology can reverse chemotherapy resistance in lung cancer. The study, published in Molecular Therapy Oncology, shows that disabling the NRF2 gene restores drug sensitivity and slows tumor growth, offering new hope for patients with treatment-resistant cancers.
The research represents the culmination of more than a decade of investigation into the NRF2 gene, a known driver of treatment resistance. 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."
Targeting Lung Squamous Cell Carcinoma
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.
The research team 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 by managing cellular stress.
Using CRISPR/Cas9, the team engineered lung cancer cells with the R34G mutation and successfully knocked out NRF2. This intervention 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.
Broad Therapeutic Implications
While the research centered on lung squamous cell carcinoma, the implications extend far beyond this single cancer type. 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."
Precision Editing with Clinical Feasibility
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."
Transformational Approach to Drug Resistance
Eric Kmiec, Ph.D., senior author of the study and executive director of the Gene Editing Institute, emphasized the paradigm-shifting nature of the approach. "This work brings transformational change to how we think about treating resistant cancers," Kmiec said. "Instead of developing entirely new drugs, we are using gene editing to make existing ones effective again."
The strategy represents a fundamental shift from traditional drug development approaches, leveraging gene editing technology to restore the effectiveness of established chemotherapy regimens rather than requiring entirely new therapeutic compounds.
