In the lab, CRISPR-Cas9 gene editing has been used to knock out an important gene in lung cancer cells, rendering them susceptible to chemotherapy.
The work, described and published in Molecular Therapy Oncolytics, used CRISPR to knock out a gene called NRF2 in the A549 lung cancer cell line. The scientists then tested the sensitivity of the cells to carboplatin and cisplatin, both in a dish and when implanted into mouse models, and found that knocking out NRF2 with CRISPR increased sensitivity to these drugs.
“NRF2 is a complex gene, but we think it is a good candidate (for targeting). It is the main regulator of chemotherapy resistance in lung cancer,” said Eric Kmeic, PhD, director of the Gene Editing Institute at Christiana Care Health System, Wilmington, Delaware, and lead author of the study, in an interview with Cancer Therapy Advisor.
Lung cancer remains one of the biggest challenges for cancer therapeutics, with many patients quickly becoming resistant to standard chemotherapies. New immunotherapies only seem to show promise in a small subset of patients and even then, have not demonstrated they have a substantial impact on long-term survival.
“Keytruda works on a subset of about 19% of patients, giving them 3-4 months. The chemo works – the CRISPR just makes it more sensitive. We want to reduce the amount of chemo needed, make it more tolerable,” said Dr Kmeic.
Dr Kmeic believes that targeting NRF2 might be particularly useful in patients with non-small cell lung cancer who are KRAS+, a subgroup where standard treatment fails completely. However, he isn’t suggesting that CRISPR-targeted gene knockouts alone are currently a personal aspiration.