Disrupting autorepression circuitry generates “open-loop lethality” to yield escape-resistant antiviral agents

Chaturvedi, Sonali; Pablo, Michael; Wolf, Marie; Rosas-Rivera, Daniel; Calia, Giuliana; Kumar, Arjun J; Vardi, Noam; Du, Kelvin; Glazier, Joshua; Ke, Ruian; Chan, Matilda F.; Perelson, Alan S.; Weinberger, Leor S.

doi:10.1016/j.cell.2022.04.022

Cited by 8 publications

(4 citation statements)

References 123 publications

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“…With the advent of RNA vaccines ( 46 ), nucleotide therapies are on the rise. Recently, feedback-disruptive DNA therapy was suggested for treating human viral infections ( 47 ). Our findings suggest that DNA therapy may also be relevant to treating drug-resistant cancer.…”

Section: Discussionmentioning

confidence: 99%

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

Wan,

Mu,

Krzysztoń

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Section: Discussionmentioning

confidence: 99%

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

Wan,

Mu,

Krzysztoń

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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“…Relying on the DNA-PK activation-dependent intrinsic immune response to IFN regulatory factor 3 (IRF-3) [ 94 , 95 ], the combined DNA-PK inhibitors blocked DNA-PK pathway and decreased IRF-3 to promote the proliferation and expansion of OV M1 in tumor cells. In a recent study, the Weinberger group [ 96 ] proposed a strategy to disrupt the feedback loop of herpesviruses using an engineered DNA duplex, causing the host cell to “overload” and die and also dismantling the barrier to drug resistance.…”

Section: Ov-activated Immune Responses For Realizing Immunotherapymentioning

confidence: 99%

Emerging Nano-/Biotechnology Drives Oncolytic Virus-Activated and Combined Cancer Immunotherapy

et al. 2023

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Oncolytic viruses (OVs) as one promising antitumor methods have made important contributions to tumor immunotherapy, which arouse increasing attention. They provide the dual mechanisms including direct killing effect toward tumor cells and immune activation for elevating antitumor responses, which have been proved in many preclinical studies. Especially, natural or genetically modified viruses as clinical immune preparations have emerged as a new promising approach objective to oncology treatment. The approval of talimogene laherparepvec (T-VEC) by the U.S. Food and Drug Administration (FDA) for the therapy of advanced melanoma could be considered as a milestone achievement in the clinical translation of OV. In this review, we first discussed the antitumor mechanisms of OVs with an emphasis on targeting, replication, and propagation. We further outlined the state of the art of current OVs in tumor and underlined the activated biological effects especially including immunity. More significantly, the enhanced immune responses based on OVs were systematically discussed from different perspectives such as combination with immunotherapy, genetic engineering of OVs, integration with nanobiotechnology or nanoparticles, and antiviral response counteraction, where their principles were shed light on. The development of OVs in the clinics was also highlighted to analyze the actuality and concerns of different OV applications in clinical trials. At last, the future perspectives and challenges of OVs as an already widely accepted treatment means were discussed. This review will provide a systematic review and deep insight into OV development and also offer new opportunities and guidance pathways to drive the further clinical translation.

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“…Recent advances in live cell fluorescence imaging platforms have led to increasing focus on studying the dynamics of biological processes and the underlying molecular mechanisms in living cells. 48 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 Nevertheless, disruptions in the external environment can perturb the delicate balance of cellular activities and exacerbate internal imbalances in yeast cells, as living cells are complex non-equilibrium microsystems. 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 Therefore, quantifying these underlying cell fate decisions in response to external stimuli remains a significant challenge.…”

Section: Introductionmentioning

confidence: 99%

Global quantitative understanding of non-equilibrium cell fate decision-making in response to pheromone

Li,

Liu,

Wang

et al. 2023

iScience

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Disrupting autorepression circuitry generates “open-loop lethality” to yield escape-resistant antiviral agents

Cited by 8 publications

References 123 publications

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

Emerging Nano-/Biotechnology Drives Oncolytic Virus-Activated and Combined Cancer Immunotherapy

Global quantitative understanding of non-equilibrium cell fate decision-making in response to pheromone

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