Science 364, eaat6982 (2019)

Cancer cells differ from normal cells by the constitutive activation of signaling pathways such as ErbB. However, the ability to selectively modulate or kill cancer cells without altering normal cell activity remains difficult. Chung et al. developed a synthetic circuit called RASER that is selectively activated in cells with constitutive ErbB activity to trigger customizable outputs. The RASER system operates by recruiting two proteins to activated ErbB: the hepatitis C virus (HCV) protease and a cargo protein anchored to the membrane via a protease substrate sequence. Chung et al. showed that cargo was released in cancer cells with elevated ErbB activity, but not in cells with normal ErbB activity even in the presence of the activating ligand EGF. They then used the RASER system to selectively target ErbB-positive cancer cells using the BH3 domain of BID to promote apoptosis or CRISPR–Cas9 domains to alter endogenous gene expression. Finally, delivery of RASER using a non-integrating virus selectively ablated ErbB-positive cancer cells. Overall, the RASER system offers a new way to selectively alter cellular outputs in oncogenic cells for therapeutic or engineering applications.