Accounting for more than one fourth of cancer deaths, lung cancer is the leading cause of cancer mortality in the United States. Increasing chemotherapy drug resistance is one of the reasons behind the deadliness of this disease. Drug resistance occurs because of the upregulation of various genes in charge of drug inactivation. One of the most troublesome of these genes is nuclear factor erthroid 2-related factor (Nfr2), which controls 100 to 200 target genes and sometimes eliminates their response to chemotherapy.
Researchers at the Helen F. Graham Cancer Center & Research Institute at Christiana Care Health System have discovered a CRISPR-Cas9 gene-editing system that can potentially reverse chemotherapy resistance by deleting a gene in tumors that causes drug tolerance. In the study, published in Molecular Therapy Oncolytics, the investigators administered chemotherapy in conjunction with CRISPR-Cas9 to mice with tumors. This combination shrunk tumors due to CRISPR-Cas9's ability to disable NFR2.
CRISPR, an acronym for "clustered regularly interspaced short palindromic repeats," was initially discovered as a defense mechanism used in bacteria to recognize and slice up DNA of invading viruses. Investigators later discovered how to manipulate CRISPR to find and remove specific DNA sequences in order to control cell biology. Cas9 acts as a pair of scissors; with the aid of CRISPR, it cuts out certain DNA sequences.
"Our goal is to see if CRISPR can be used with chemotherapy to provide a safe, affordable way to give patients who are not responding to treatment at least a fighting chance against this very challenging cancer," commented Eric Kmiec, Ph.D, principal author of the study and Director of the Gene Editing Institute. "We believe that finding ways to use CRISPR to improve existing treatments will lead to some of the first benefits for patients while we tackle the vital ethical issues around the use of CRISPR for edits that can be passed on through DNA. This is an exciting step in the journey of exploring the health benefits of gene editing."
For More Information
Bialk P, Wang Y, Banas K & Kmiec EB (2018). Functional gene knockout of NRF2 increases chemosensitivity of human lung cancer A549 cells in vitro and in a xenograft mouse model. Mol Ther Oncolytics, 11:75-89. DOI:10.1016/j.omto.2018.10.002
Image courtesy of Yale Rosen