A compact synthetic pathway rewires cancer signaling to therapeutic effector release

Hokyung K Chung; Xinzhi Zou; Bryce T Bajar; Veronica R Brand; Yunwen Huo; Javier F Alcudia; James E Ferrell Jr; Michael Z Lin

doi:10.1126/science.aat6982

A compact synthetic pathway rewires cancer signaling to therapeutic effector release

Science. 2019 May 3;364(6439):eaat6982. doi: 10.1126/science.aat6982.

Authors

Hokyung K Chung^{1

2

3}, Xinzhi Zou⁴, Bryce T Bajar^{3

4}, Veronica R Brand^{3

4}, Yunwen Huo^{2

3

4}, Javier F Alcudia⁵, James E Ferrell Jr⁶, Michael Z Lin^{7

3

4

6}

Affiliations

¹ Department of Biology, Stanford University, Stanford, CA, USA.
² Department of Neurobiology, Stanford University, Stanford, CA, USA.
³ Department of Pediatrics, Stanford University, Stanford, CA, USA.
⁴ Department of Bioengineering, Stanford University, Stanford, CA, USA.
⁵ Neuroscience Gene Vector and Virus Core, Stanford University, Stanford, CA, USA.
⁶ Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA.
⁷ Department of Neurobiology, Stanford University, Stanford, CA, USA. mzlin@stanford.edu.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenoviridae
Apoptosis / genetics*
Bioengineering / methods*
CRISPR-Associated Protein 9
CRISPR-Cas Systems
Cell Line, Tumor
Endopeptidases / genetics
Humans
Models, Theoretical
Neoplasms / genetics*
Neoplasms / pathology
Neoplasms / therapy*
Protein Stability
Proteolysis
Receptor, ErbB-2 / antagonists & inhibitors*
Receptor, ErbB-2 / genetics*
Receptor, ErbB-2 / metabolism
Signal Transduction
Synthetic Biology
Transcription, Genetic
Viral Nonstructural Proteins / genetics

Substances

NS3 protein, hepatitis C virus
Viral Nonstructural Proteins
ERBB2 protein, human
Receptor, ErbB-2
CRISPR-Associated Protein 9
Endopeptidases
TEV protease

Abstract

Publication types

MeSH terms

Substances

Grants and funding