Adaptive DNA amplification of synthetic gene circuit opens a way to overcome cancer chemoresistance
Menée sur des lignées de cellules de mammifères modifiées par ingénierie pour développer une résistance à la puromycine, cette étude met en évidence le rôle des amplifications d'ADN dans la résistance thérapeutique et démontre que des oligonucléotides TFO (Triplex-forming oligonucleotide) ciblant des régions amplifiées de l'ADN peuvent lever cette résistance
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.