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Thoracic

P25: CRISPR Directed Gene Editing of NRF2 in Squamous Lung Cancer (A Novel Approach to Overcoming Drug Resistance)

    ePoster Presenter(s)

  • Khea Tan, MD (she/her/hers)

    General Surgery Resident
    Hackensack Meridian Jersey Shore University Medical Center, New Jersey, United States

    • Author(s)

  • KB

    Kelly Banas, PhD

    Principal Investigator
    Gene Editing Institute ChristianaCare, United States

  • NH

    Nicole Haas, MS

    Staff Scientist
    Gene Editing Institute ChristianaCare, United States

  • NR

    Natalia Rivera-Torres, PhD

    Principal Investigator
    Gene Editing Institute ChristianaCare, United States

  • PB

    Pawel Bialik, MS

    Principal Investigator
    Gene Editing Institute ChristianaCare, United States

  • BA

    Brittany Al-Atrache, MD

    General Surgery Resident
    Hackensack Meridian Jersey Shore University Medical Center, United States

  • GT

    Gregory Tiesi, MD, FACS, FSSO

    Medical Director of Hepatobiliary Surgery
    Hackensack Meridian Jersey Shore University Medical Center
    Neptune, New Jersey, United States

  • EK

    Eric Kmiec, PhD

    Executive Director and Chief Scientific Officer
    Gene Editing Institute ChristianaCare, United States

Introduction: Resistance to chemotherapy is a major problem in cancer treatment and has profound effects on outcomes. NRF2 is a master regulatory gene known to control the response to cancer therapy conferring resistance to chemotherapy, radiation therapy and immunotherapy. Utilizing a novel approach for CRISPR/Cas gene editing, we sought to evaluate if disabling the NRF2 gene could significantly reduce chemoresistance.

Methods: A CRISPR/Cas9 complex was developed to target the NRF2 gene, via the R34G mutation, in a patient derived subcutaneous xenograft squamous cell lung cancer model. The CRISPR/Cas9 complex was delivered by an adenoviral vector via direct tumor injection.

Results:

Mice were intratumorally injected on days 0, 2 and 7 with R34G-Cas9 or a non-specific scrambled Cas9 versus control. All mice received intravenous low-dose chemotherapy (carboplatin plus paclitaxel) on days 3 and 10. Survival was tracked up to 50 days post initial intratumoral injection. All groups consisted of n = 12 mice. Group 1 received R34G-Cas9 with 12.5mg/kg carboplatin and 5mg/k paclitaxel. Median overall survival time was not reached as none of the mice died within the observation period (overall survival = 100%). Group 2 received scrambled-Cas9 with 12.5mg/kg carboplatin and 5mg/k paclitaxel. Median overall survival time was 33 days with an overall survival of 33% for the experiment. Group 3 received chemotherapy alone. Median OS time was also 33 days with an overall survival of 42%. Overall survival in Group 1 was statistically significantly longer compared to both groups (p < 0.5). (Figure 1)


Conclusions: CRISPR-Cas9 editing of NRF2, in an in vivo PDX mouse model, led to decreased chemoresistance and marked improvement in overall survival. To our knowledge, our tumor specific gene editing to restore drug activity is the first of its kind ever reported.

Learning Objectives:

  • Identify genes associated with chemoresistance in cancer
  • Identify the effect of gene silencing on sensitivity to chemotherapy for squamous cell lung cancer
  • Interpret the significance of gene editing for augmentative cancer therapy