A new study on lung squamous cell carcinoma shows NRF2 overactivity drives chemotherapy resistance, and knocking out NRF2 re-sensitizes tumors to drugs like carboplatin and paclitaxel.

Researchers at ChristianaCare’s Gene Editing Institute used CRISPR/Cas9 to disable NRF2 in lung cancer models, reversing resistance and slowing tumor growth.

Targeting a tumor-specific NRF2 mutation (R34G) with CRISPR/Cas9 restored sensitivity to standard chemotherapy in cells and improved treatment response in animal models.

The work is positioned as a potential paradigm shift, aiming to enhance existing therapies through precise gene editing rather than developing new drugs.

ChristianaCare’s Gene Editing Institute is presented as a leader in CRISPR research within a community health system, with a focus on fast-tracking discoveries to patients safely and precisely.

The project integrates clinical context through a community-based framework to accelerate bench-to-bedside translation while upholding safety in gene-editing therapies.

A lipid nanoparticle (LNP) delivery system achieved robust genome editing in both engineered and patient-derived tumor models, supporting clinical development feasibility.

The study is documented in Molecular Therapy Oncology (2025) with Kelly H. Banas et al. and the DOI provided.

Senior author Eric Kmiec and lead author Kelly Banas emphasize this approach re-sensitizes tumors to existing drugs, potentially improving outcomes and tolerability without new chemotherapeutics.

The work is described as a transformational shift in treating resistant cancers by using gene editing to restore sensitivity to standard therapies rather than creating new drugs.

The authors highlight that gene editing can make current chemotherapy effective again, aligning with better tolerability for patients.

The study underscores the promise of precision CRISPR therapies that minimize genomic side effects while restoring chemotherapy effectiveness.

CorriXR’s lead programs in HNSCC and LUSC are supported by IND-enabling work and collaboration with ChristianaCare’s Gene Editing Institute to advance toward FDA IND applications.

Lead author Kelly Banas notes the findings lay a strong foundation for clinical trials and potential applicability to other NRF2-driven resistant tumors.

CorriXR aims to advance gene-editing strategies to restore effectiveness of existing therapies, potentially enabling lower chemotherapy doses and reduced toxicity.

The study envisions translating gene-editing approaches into patient-ready therapies within a community-based Institute setting.

Notably, disrupting NRF2 in only 20%–40% of tumor cells was sufficient to enhance response and shrink tumors, suggesting clinical feasibility without complete editing.

Partial editing (20%–40%) yielded meaningful treatment gains, indicating potential for real-world application where full editing is unlikely.

The November 14 publication in Molecular Therapy Oncology reports these findings across multiple in vitro lung cancer lines and in vivo models with consistent results.

Findings come from diverse models, including several lung cancer cell lines and animal studies, reinforcing reproducibility.

The work builds on more than a decade of NRF2 research and aims to move NRF2-targeted gene editing toward clinical trials for resistant cancers.

Non-viral lipid nanoparticles delivered the CRISPR edits in mice, achieving high specificity to mutated NRF2 with minimal off-target effects.

Off-target edits remained under 0.2%, signaling a favorable safety profile for the LNP-delivered approach.

Authors suggest this CRISPR-based strategy could re-sensitize multiple solid tumors to standard chemotherapy, potentially broadening impact beyond lung cancer.

The full publication details are available in Molecular Therapy Oncology, with the article published online on ScienceDirect.

Overall, NRF2 is presented as a master regulator of resistance, with the institute’s decade-long focus underpinning this breakthrough.

Edited tumors showed reduced NRF2 signaling, evidencing effective disruption of the NRF2 pathway.