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Functional characterization of tumor-specific CRISPR-directed gene editing as a combinatorial therapy for the treatment of solid tumors

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Titel: Functional characterization of tumor-specific CRISPR-directed gene editing as a combinatorial therapy for the treatment of solid tumors
Autoren: Kelly H. Banas, Pawel A. Bialk, Natalia Rivera-Torres, Katelynn Owens, Tori N. Reiner, Kristen M. Pisarcik, Nicole Haas, Emily Gielda, Komal Khan, Krishna Priya Narra, Eric B. Kmiec
Quelle: Molecular Therapy: Oncology, Vol 33, Iss 4, Pp 201079- (2025)
Verlagsinformationen: Elsevier, 2025.
Publikationsjahr: 2025
Bestand: LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Schlagwörter: MT: Regular Issue, CRISPR-Cas9, gene editing, NRF2, drug resistance, chemosensitivity, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Beschreibung: As we pursue clinical applications for CRISPR-directed gene editing in overcoming resistance to anticancer drugs, we have focused on genetic disruption of the transcription factor, NRF2, a master regulator of cellular stress and detoxification. The level of NRF2 in tumor cells is often a clear determinant of the effectiveness of standard of care. We began to craft a therapeutic approach using tumor-specific CRISPR editing, building upon our previous work elucidating the effect of NRF2 knockout. We selected a prevalent mutation, R34G, that occurs in the Neh2 domain of NRF2, which has been shown to disrupt KEAP1-mediated degradation, thus impacting the NRF2-KEAP1 pathway. Here, we take a global approach by assessing the genomic, transcriptomic, proteomic, and phenotypic profile of a CRISPR-targeted population of cells, both in vitro and in vivo. We detail the design and generation of a clinically relevant cell model and its translation into an animal model, characterizing the efficacy of disabling NRF2 concomitant with the restoration of chemosensitivity. We demonstrate that 20%–40% gene editing activity is sufficient to improve response to chemotherapy in animal models. We suggest that understanding the genetic diversity of CRISPR outcomes must be a key consideration in identifying effective CRISPR molecules for clinical application.
Publikationsart: article
Dateibeschreibung: electronic resource
Sprache: English
ISSN: 2950-3299
Relation: http://www.sciencedirect.com/science/article/pii/S2950329925001481; https://doaj.org/toc/2950-3299
DOI: 10.1016/j.omton.2025.201079
Zugangs-URL: https://doaj.org/article/3da819371b5840958efd7c3780d9372a
Dokumentencode: edsdoj.3da819371b5840958efd7c3780d9372a
Datenbank: Directory of Open Access Journals
Beschreibung
Abstract:As we pursue clinical applications for CRISPR-directed gene editing in overcoming resistance to anticancer drugs, we have focused on genetic disruption of the transcription factor, NRF2, a master regulator of cellular stress and detoxification. The level of NRF2 in tumor cells is often a clear determinant of the effectiveness of standard of care. We began to craft a therapeutic approach using tumor-specific CRISPR editing, building upon our previous work elucidating the effect of NRF2 knockout. We selected a prevalent mutation, R34G, that occurs in the Neh2 domain of NRF2, which has been shown to disrupt KEAP1-mediated degradation, thus impacting the NRF2-KEAP1 pathway. Here, we take a global approach by assessing the genomic, transcriptomic, proteomic, and phenotypic profile of a CRISPR-targeted population of cells, both in vitro and in vivo. We detail the design and generation of a clinically relevant cell model and its translation into an animal model, characterizing the efficacy of disabling NRF2 concomitant with the restoration of chemosensitivity. We demonstrate that 20%–40% gene editing activity is sufficient to improve response to chemotherapy in animal models. We suggest that understanding the genetic diversity of CRISPR outcomes must be a key consideration in identifying effective CRISPR molecules for clinical application.
ISSN:29503299
DOI:10.1016/j.omton.2025.201079