, have reported new preclinical findings describing the use of CRISPR-based genome modification to counteract chemotherapy resistance in squamous cell lung carcinoma (LUSC).){kind=link}
Researchers from CorriXR Therapeutics, in collaboration with ChristianaCare’s Gene Editing Institute (GEI), have reported new preclinical findings describing the use of CRISPR-based genome modification to counteract chemotherapy resistance in squamous cell lung carcinoma (LUSC). The work, now published in Molecular Therapy Oncology, examines whether selective disruption of NRF2, a transcription factor long associated with stress-response signaling and drug-resistant tumor phenotypes, can restore sensitivity to standard chemotherapeutic agents.
According to the authors, the study builds on a substantial body of GEI research into NRF2’s role in shaping tumor behavior, particularly its capacity to confer broad resistance across solid tumors. Eric B. Kmiec, Ph.D., who leads both CorriXR Therapeutics and the GEI, noted that the results are consistent across cell-based experiments and murine tumor models, suggesting that NRF2-directed editing may form a practical basis for future translational studies.
This foundational work strengthens CorriXR’s strategy of disrupting cancer cell survival pathways to restore sensitivity to standard therapies. These findings build on more than a decade of GEI research into NRF2, a master regulator of cellular stress responses and known driver of treatment resistance. We are encouraged by the consistency of results across in vitro human lung cancer models and our in vivo studies and are actively pursuing IND-enabling work to bring this promising approach to patients.
Eric B. Kmiec, Ph.D., Founder and Chief Executive Officer of CorriXR Therapeutics and Executive Director of GEI
The reported findings include several experimentally supported observations:
- Partial editing was sufficient to shift tumor response: Disrupting NRF2 in roughly one-fifth to two-fifths of malignant cells generated a measurable increase in chemosensitivity, accompanied by slower tumor progression in animal models.
- Downstream signaling changes: Tumors exposed to the editing strategy displayed marked reductions in NRF2 expression and in the activity of associated stress-response markers, aligning with the proposed mechanism of action.
- Low off-target signal: Off-target edits remained near background levels (below 0.2%), an important consideration as gene-editing approaches move toward potential clinical evaluation.
- Feasibility of lipid nanoparticle delivery: The investigators report that a lipid nanoparticle platform produced effective delivery and editing in both engineered and patient-derived models, a key requirement for translation beyond traditional laboratory systems.
Kelly Banas, Ph.D., the study’s lead author at GEI, emphasized that resistance to cytotoxic therapy continues to limit outcomes for patients with LUSC and other solid tumors. She noted that, based on the reported data, attenuating NRF2 activity could allow for lower chemotherapy dosing while maintaining antitumor efficacy, though this remains to be demonstrated clinically.
Treatment resistance remains one of the greatest challenges in oncology, and these data demonstrate that targeting NRF2 can meaningfully resensitize tumors with minimal off-target effects. This approach has the potential to lower chemotherapy doses, reduce toxicity and help patients remain healthier throughout treatment.
Kelly Banas, Ph.D., lead author of the study and Associate Director of Research at GEI.
The authors also point out that NRF2-driven resistance is not unique to lung cancer. Kmiec highlighted evidence that similar mechanisms contribute to treatment failures in head and neck squamous cell carcinoma and other tumor types, underscoring potential applicability beyond the present study.
LUSC accounts for roughly one-quarter of non-small cell lung cancer diagnoses in the United States. Many patients ultimately progress despite chemotherapy, in part due to NRF2-mediated survival signaling. As no targeted therapies currently address this resistance mechanism, the approach described in the publication may represent a conceptual shift.
CorriXR Therapeutics and GEI report that they are now conducting independent validation studies through contract research organizations and initiating regulatory-required safety evaluations to support a future Investigational New Drug (IND) application with the U.S. Food and Drug Administration. The groups also indicate that they are exploring collaborations to accelerate clinical translation of their LUSC and HNSCC programs.