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Biomarker-Guided Development of DNA Repair Inhibitors
James M Cleary1, Andrew J Aguirre2, Geoffrey I Shapiro3
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Abstract:
Anti-cancer drugs targeting the DNA damage response (DDR) exploit genetic or functional defects in this pathway through synthetic lethal mechanisms. For example, defects in homologous recombination (HR) repair arise in cancer cells through inherited or acquired mutations in BRCA1, BRCA2, or other genes in the Fanconi anemia/BRCA pathway, and these tumors have been shown to be particularly sensitive to inhibitors of the base excision repair (BER) protein poly (ADP-ribose) polymerase (PARP). Recent work has identified additional genomic and functional assays of DNA repair that provide new predictive and pharmacodynamic biomarkers for these targeted therapies. Here, we examine the development of selective agents targeting DNA repair, including PARP inhibitors; inhibitors of the DNA damage kinases ataxia-telangiectasia and Rad3 related (ATR), CHK1, WEE1, and ataxia-telangiectasia mutated (ATM); and inhibitors of classical non-homologous end joining (cNHEJ) and alternative end joining (Alt EJ). We also review the biomarkers that guide the use of these agents and current clinical trials with these therapies.
Insights
Targeting cancer
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Cancer cells with DNA repair defects, such as homologous recombination (HR) deficiency due to BRCA mutations, are vulnerable to synthetic lethality.
- Poly (ADP-ribose) polymerase (PARP) inhibitors are effective against HR-deficient tumors by exploiting base excision repair (BER) pathway defects.
Purpose of the Study:
- To review the development of novel DNA damage response (DDR) targeted therapies.
- To discuss predictive and pharmacodynamic biomarkers for these agents.
- To summarize current clinical trials involving DDR inhibitors.
Main Methods:
- Review of selective agents targeting DNA repair pathways.
- Examination of inhibitors including PARP, ATR, CHK1, WEE1, ATM, cNHEJ, and Alt EJ.
- Analysis of biomarkers and clinical trial data.
Main Results:
- Development of targeted therapies exploiting DDR defects offers new anti-cancer strategies.
- Biomarkers are crucial for identifying sensitive patient populations and monitoring treatment response.
- Multiple DDR inhibitors are in various stages of clinical development.
Conclusions:
- Targeted therapies inhibiting DNA repair pathways represent a promising approach in oncology.
- Biomarker-driven strategies are essential for optimizing the efficacy of these novel anti-cancer agents.
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