Microscopy image of RAS-sensor proteins (with a yellow fluorescent protein marker) binding to the over-activated RAS oncogene on the membrane of cells (blue).
All cancers are caused by changes in genes. One of the most frequently mutated genes is RAS, which plays a central role in cell signalling. RAS mutations are found in around 19 per cent of cancer patients worldwide and are responsible for nearly 1.9 million cancer-related deaths per year.
Mutated RAS proteins continuously send growth signals to cells, which can cause them to grow uncontrollably and become cancerous. Although recently developed treatments known as RAS inhibitors can target specific RAS cancers, their therapeutic success remains limited.
Synthetic biology – an interdisciplinary field that applies engineering principles to biology – offers a powerful alternative. It enables the design of synthetic gene circuits that can sense and respond to genetic mutations. These circuits can be engineered to detect cancer-specific biomarkers and produce therapeutic proteins that selectively target cancer cells. However, achieving high selectivity for cancer cells while avoiding toxicity in healthy cells remains a major challenge.
To address this problem, Senn, Nissen and Benenson used synthetic biology to develop DNA-encoded therapeutics for RAS-driven cancers. The researchers created two circuits for sensing RAS-specific inputs: sensors that bind directly to RAS and sensors that detect RAS-specific signals. By combining these sensors, they created circuits with unprecedented selectivity for cells carrying RAS mutations, while showing minimal activity in healthy cells.
Moreover, their modular design could be adapted to specific cell lines to optimise selectivity and fine-tune expression levels. The circuits were tested in multiple RAS-driven cancer cell lines and showed therapeutic potential by driving expression of a clinically relevant protein that successfully killed cancer cells with RAS mutations.
Overall, the study by Senn et al. highlights the potential of synthetic gene circuits as a modular and adaptable strategy for targeting cancer. By developing RAS-specific sensors and integrating them into selective circuits, the researchers lay the groundwork for new therapies against RAS-driven cancers that could benefit millions of patients. While clinical application will require improved delivery systems and validation in patient-derived models, this work demonstrates how synthetic gene circuits could help overcome key challenges in cancer therapy.
