Large-scale drug atlas uncovers new genome editing modulators and potential therapeutic strategies for DNA repair-deficient cancers
Scientists uncover how common medicines may influence CRISPR therapy outcomes and precision cancer treatment.
© Philipp Kanis (image created using ChatGPT)
To the point
- A comprehensive catalog of drug-DNA repair interactions: The study describes how more than 2,000 approved pharmaceuticals influence genome editing outcomes, creating a valuable resource for translational and therapeutic applications.
- Clinically safe editing modulators: The screen uncovers pharmaceuticals capable of enhancing or suppressing mutational outcomes across major DNA repair pathways.
- New players in DNA repair regulation: Two proteins, estrogen receptor 2 (ESR2) and aldehyde oxidase 1 (AOX1) emerge as previously unrecognized modulators of DNA repair pathway choice, revealing unexpected biological roles.
- Opportunities for precision oncology: Several identified drugs selectively target cancer cells with inherent DNA repair defects, potentially broadening the therapeutic toolbox for DNA repair-based cancer strategies.
In a new study, scientists at the Max Planck Institute for Evolutionary Anthropology in Leipzig analyzed the impact of over 2,000 clinically approved drugs on DNA repair and CRISPR genome editing outcomes. They found compounds that can be used to improve genome editing, molecules that selectively kill cultured cancer cells, and further identified novel roles in DNA repair for two proteins.
DNA double-strand breaks are crucial lesions in the genome that can be repaired in several ways. Some repair processes act quickly and introduce additional mutations at the lesion site, while others take longer but allow for precise correction. These pathways can be exploited in genome editing to introduce mutations into human cells. This involves cutting the DNA at a specific location in the genome using programmable CRISPR-Cas gene scissors. The resulting break must be repaired by the cells in order for them to survive, and researchers can provide a DNA template carrying the desired mutation. The efficiency with which this mutation is incorporated largely depends on the activity of the repair pathway, calling for tools to inhibit competing pathways to increase the efficiency of the desired outcome.
A team of scientists at the Max Planck Institute for Evolutionary Anthropology investigated the effects of FDA-approved drugs on the selection of DNA repair pathways. "Understanding how everyday medicines interact with CRISPR-based treatments will be increasingly important as these therapies enter real-world clinical use," says Dominik Macak, one of the study's lead authors. With the first CRISPR gene therapy approved in the US, UK, and EU in late 2023, patients receiving such treatments may also be taking common drugs for infection or chronic conditions. Some of these routine medications can influence cellular processes such as DNA repair that may, in turn, affect how well a therapy works or how safely it performs.
More than 2,000 pharmaceuticals tested
The scientists created a comprehensive atlas showing how clinically approved drugs affect the way human cells repair broken DNA. They tested more than 7,000 drug conditions to determine how each compound alters the choice of DNA repair after a targeted CRISPR cut. "We anticipate that this catalog will serve as a valuable resource for clinicians and researchers working in disease modelling, gene therapy and oncology," adds co-lead author Philipp Kanis.
Novel players in DNA repair regulation discovered
The team found several pharmaceuticals that can influence major repair pathways. Using the screening data, they further explored previously unrecognized drug targets that most strongly influence repair outcomes. Notably, they uncovered novel roles in DNA repair for two proteins not previously associated with genome editing. These proteins are estrogen receptor 2 (ESR2) and aldehyde oxidase 1 (AOX1). Targeted inhibition of ESR2 can increase efficiency of precise edits by up to fourfold, while drugs that inhibit AOX1 can be used to kill cultured cancer cells, which lack one repair pathway - a condition that applies to many cancer cells. "Our study identifies several approved medicines as promising candidates for treating cancers with DNA-repair deficiencies, offering potential options beyond current therapies," says Stephan Riesenberg, senior researcher on the project. "Nevertheless, additional research is needed to validate if our findings obtained from experiments with cultured cells would actually translate to real-world medical use."
