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Targeting Genome Maintenance Defects of Cancers Using Chain-Terminating Nucleoside Analogs
Ryotaro Kawasumi1, Rubaiat E Tabassum1, Kouji Hirota1
1Department of Chemistry, Graduate School of Science, Tokyo Metropolitan University, Tokyo, Japan.
Abstract:
Conventional cancer therapies, including radiation therapy and chemotherapy, rely on inflicting DNA damage, yet they inevitably affect normal cells, leading to severe adverse effects. The advent of precision chemotherapy exploiting tumor-specific DNA repair defects has validated the effectiveness of this approach. The first successful example is PARP inhibitors, which selectively kill homologous recombination (HR) defective cancers, such as familial breast cancer possessing HR deficiency due to BRCA gene mutations. However, the broader landscape of DNA maintenance-including DNA replication, repair, and checkpoint pathways-harbors numerous mutations in tumors that remain untargeted. Here, we propose repurposing chain-terminating nucleoside analogs (CTNAs) to target such cancers' vulnerabilities. CTNAs, long utilized as anti-cancers and anti-viral drugs, inhibit replication and thereby suppress growth, but their activity has never been systematically aligned with specific cancer mutations associated with DNA maintenance defects. Based on our recent studies, we demonstrate that CTNAs elicit synthetic lethality in cells deficient for distinct DNA maintenance systems, amplifying replication stress, leading to cell death. We highlight the spectrum of CTNA-induced lesions and repair pathways required for cellular tolerance. This framework presents a versatile "repair-defect-guided" chemotherapy that expands the clinical utility of CTNAs and improves therapeutic effect by reducing side effects.
Insights
New chemotherapy repurposes chain-terminating nucleoside analogs (CTNAs) to target cancer DNA repair defects. This precision approach exploits tumor vulnerabilities, enhancing efficacy and reducing side effects for better cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Conventional cancer therapies cause DNA damage, affecting normal cells and leading to adverse effects.
- Precision chemotherapy leverages tumor-specific DNA repair defects, exemplified by PARP inhibitors for BRCA-mutated cancers.
- Numerous tumor mutations in DNA maintenance pathways remain therapeutically untargeted.
Purpose of the Study:
- To propose repurposing chain-terminating nucleoside analogs (CTNAs) to target cancer vulnerabilities arising from DNA maintenance defects.
- To demonstrate CTNAs elicit synthetic lethality in cells with specific DNA maintenance deficiencies.
- To establish a "repair-defect-guided" chemotherapy framework for CTNAs.
Main Methods:
- Investigated the effects of CTNAs on cancer cells with distinct DNA maintenance deficiencies.
- Analyzed CTNA-induced DNA lesions and cellular repair pathways.
- Evaluated the therapeutic potential of CTNAs in a precision medicine context.
Main Results:
- CTNAs induce synthetic lethality in cells deficient in specific DNA maintenance systems.
- CTNAs amplify replication stress, leading to cancer cell death.
- Identified CTNA-induced lesions and essential repair pathways for cellular tolerance.
Conclusions:
- CTNAs can be repurposed as a versatile chemotherapy agent guided by cancer-specific DNA repair defects.
- This approach expands the clinical utility of CTNAs by targeting a broader range of mutations.
- Repair-defect-guided CTNA therapy offers improved therapeutic effects with potentially reduced side effects.
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