Adaptive DNA amplification of synthetic gene circuit opens a way to overcome cancer chemoresistance.

Abstract

Drug resistance continues to impede the success of cancer treatments, creating a need for experimental model systems that are broad, yet simple, to allow the identification of mechanisms and novel countermeasures applicable to many cancer types. To address these needs, we investigated a set of engineered mammalian cell lines with synthetic gene circuits integrated into their genome that evolved resistance to Puromycin. We identified DNA amplification as the mechanism underlying drug resistance in 4 out of 6 replicate populations. Triplex-forming oligonucleotide (TFO) treatment combined with Puromycin could efficiently suppress the growth of cell populations with DNA amplification. Similar observations in human cancer cell lines suggest that TFOs could be broadly applicable to mitigate drug resistance, one of the major difficulties in treating cancer.

• Authors: Yiming Wan, Quanhua Mu, Rafał Krzysztoń, Joseph Cohen, Damiano Coraci, Christopher Helenek, Christopher Tompkins, Annie Lin, Kevin Farquhar, Erin Cross, Jiguang Wang, Gábor Balázsi
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 120 Issue 49 Pg. e2303114120 (Dec 05 2023) ISSN: 1091-6490 [Electronic] United States
• PMID: 38019857 (Publication Type: Journal Article)

Chemical References

• DNA
• Oligonucleotides
• Puromycin

Topics

• Animals
• Humans
• DNA (metabolism)
• Drug Resistance, Neoplasm (genetics)
• Genes, Synthetic
• Oligonucleotides
• Puromycin
• Mammals (metabolism)
• Neoplasms (drug therapy, genetics)