A compact synthetic pathway rewires cancer signaling to therapeutic effector release.
Hokyung K ChungXinzhi ZouBryce T BajarVeronica R BrandYunwen HuoJavier F AlcudiaJames E FerrellMichael Z LinPublished in: Science (New York, N.Y.) (2019)
An important goal in synthetic biology is to engineer biochemical pathways to address unsolved biomedical problems. One long-standing problem in molecular medicine is the specific identification and ablation of cancer cells. Here, we describe a method, named Rewiring of Aberrant Signaling to Effector Release (RASER), in which oncogenic ErbB receptor activity, instead of being targeted for inhibition as in existing treatments, is co-opted to trigger therapeutic programs. RASER integrates ErbB activity to specifically link oncogenic states to the execution of desired outputs. A complete mathematical model of RASER and modularity in design enable rational optimization and output programming. Using RASER, we induced apoptosis and CRISPR-Cas9-mediated transcription of endogenous genes specifically in ErbB-hyperactive cancer cells. Delivery of apoptotic RASER by adeno-associated virus selectively ablated ErbB-hyperactive cancer cells while sparing ErbB-normal cells. RASER thus provides a new strategy for oncogene-specific cancer detection and treatment.
Keyphrases
- induced apoptosis
- tyrosine kinase
- endoplasmic reticulum stress
- papillary thyroid
- signaling pathway
- crispr cas
- oxidative stress
- transcription factor
- squamous cell
- dendritic cells
- regulatory t cells
- cell death
- public health
- cancer therapy
- squamous cell carcinoma
- dna methylation
- cell cycle arrest
- bioinformatics analysis
- genome wide
- single molecule
- cell proliferation
- atrial fibrillation
- loop mediated isothermal amplification
- combination therapy
- robot assisted
- real time pcr
- minimally invasive
- replacement therapy
- label free