Large-Scale Drug Screen Reveals Common Medicines Can Enhance CRISPR Therapy and Target DNA Repair-Deficient Cancers
核心洞察
Scientists at the Max Planck Institute for Evolutionary Anthropology (搜索) analyzed over 2,000 clinically approved drugs and found compounds that can improve CRISPR genome editing outcomes and selectively kill cancer cells.
The comprehensive drug atlas identified two previously unknown DNA repair modulators, estrogen receptor 2 (ESR2 (搜索)) and aldehyde oxidase 1 (AOX1 (搜索)), with ESR2 inhibition increasing precise editing efficiency up to fourfold.
Several approved medicines showed promise for treating DNA repair-deficient cancers, potentially expanding therapeutic options beyond current treatments.
Scientists at the Max Planck Institute for Evolutionary Anthropology (搜索) in Leipzig have created a comprehensive atlas revealing how more than 2,000 clinically approved drugs influence DNA repair and CRISPR genome editing outcomes. The research identifies compounds that can enhance genome editing efficiency and molecules that selectively target cancer cells with DNA repair deficiencies.
The study tested over 7,000 drug conditions to determine how each compound alters DNA repair pathway selection after targeted CRISPR cuts. "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.
Clinical Relevance for CRISPR Therapies
With the first CRISPR gene therapy approved in the US, UK, and EU in late 2023, patients receiving such treatments may simultaneously take common drugs for infections or chronic conditions. Some routine medications can influence cellular processes like DNA repair, potentially affecting therapy efficacy and safety.
The research addresses a critical gap in understanding drug-therapy interactions. DNA double-strand breaks can be repaired through multiple pathways - some acting quickly but introducing additional mutations, while others take longer but allow precise correction. The efficiency of incorporating desired mutations largely depends on repair pathway activity, creating a need for tools to inhibit competing pathways.
Novel DNA Repair Modulators Identified
The screening uncovered previously unrecognized roles in DNA repair for two proteins: estrogen receptor 2 (ESR2 (搜索)) and aldehyde oxidase 1 (AOX1 (搜索)). Targeted inhibition of ESR2 can increase the efficiency of precise edits by up to fourfold, while drugs that inhibit AOX1 demonstrated the ability to kill cultured cancer cells lacking specific repair pathways.
"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.
Implications for Precision Oncology
The research reveals opportunities for precision cancer treatment by identifying drugs that selectively target cancer cells with inherent DNA repair defects. Many cancer cells lack functional repair pathways, making them vulnerable to specific therapeutic interventions identified in this study.
Co-lead author Philipp Kanis notes, "We anticipate that this catalog will serve as a valuable resource for clinicians and researchers working in disease modelling, gene therapy and oncology."
Future Research Directions
While the findings demonstrate significant potential, researchers emphasize the need for additional validation. "Nevertheless, additional research is needed to validate if our findings obtained from experiments with cultured cells would actually translate to real-world medical use," Riesenberg cautions.
The comprehensive drug atlas provides a foundation for future investigations into drug-DNA repair interactions, potentially informing clinical decision-making for patients receiving CRISPR-based therapies while managing other medical conditions with conventional pharmaceuticals.