Adaptive DNA amplification of synthetic gene circuit opens a way to overcome cancer chemoresistance.
Adaptive DNA amplification of synthetic gene circuit opens a way to overcome cancer chemoresistance.
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DOI：
10.1073/pnas.2303114120
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发表时间：
2023-12-05
影响因子：
11.1
通讯作者：
Balazsi, Gabor
中科院分区：
文献类型：
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作者：
Wan, Yiming;Mu, Quanhua;Krzyszton, Rafal;Cohen, Joseph;Coraci, Damiano;Helenek, Christopher;Tompkins, Christopher;Lin, Annie;Farquhar, Kevin;Cross, Erin;Wang, Jiguang;Balazsi, Gabor
癌症仍然经常抵抗治疗，这就需要对癌症耐药性和新的治疗方案有新的认识。广泛而简单的实验模型可以帮助确定耐药性的机制和制定对策。在这里，通过研究先前进化出耐药性的工程哺乳动物细胞，我们发现DNA扩增是耐药性的最常见原因。核苷酸治疗与原始药物联合有效地抑制了仓鼠和癌细胞的DNA扩增，这表明广泛适用的治疗方法可能会对抗癌症的化疗耐药。耐药性继续阻碍癌症治疗的成功，创造了对广泛而简单的实验模型系统的需求，以允许识别适用于许多癌症类型的机制和新的对策。为了满足这些需求，我们研究了一组将合成基因电路整合到其基因组中的工程哺乳动物细胞系，这些细胞系进化出对嘌呤霉素的抗性。我们发现DNA扩增是6个重复种群中4个耐药的机制。三聚体形成寡核苷酸（TFO）联合嘌呤霉素可有效抑制DNA扩增细胞群的生长。在人类癌细胞系中的类似观察表明，tfo可广泛适用于减轻耐药性，这是治疗癌症的主要困难之一。
Cancers still resist treatment too often, creating a need for new insights into cancer drug resistance and new treatment options. Experimental models that are broad, yet simple could aid with the identification of mechanisms and development of countermeasures of drug resistance. Here, by studying engineered mammalian cells that previously evolved resistance to a drug, we found DNA amplification as the most common cause of drug resistance. A nucleotide treatment combined with the original drug efficiently suppressed the growth of hamster and cancer cells with DNA amplification, suggesting broadly applicable therapies that might combat chemoresistance in cancer. 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.