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Understanding Resistance Mechanisms and Expanding the Therapeutic Utility of PARP Inhibitors
Joline S J Lim1,2, David S P Tan3,4
1Department of Hematology-Oncology, National University Cancer Institute of Singapore, National University Hospital, Singapore 119228, Singapore. joline_sj_lim@nuhs.edu.sg.
Abstract:
Poly-(ADP-ribose) polymerase (PARP) inhibitors act through synthetic lethality in cells with defects in homologous recombination (HR) DNA repair caused by molecular aberrations such as BRCA mutations, and is approved for treatment in ovarian cancer, with promising clinical activity against other HR defective tumors including breast and prostate cancers. Three PARP inhibitors have been FDA approved, while another two have shown promising activity and are in late stage development. Nonetheless, both primary and secondary resistance to PARP inhibition have led to treatment failure, and the development of predictive biomarkers and the ability to identify and overcome mechanisms of resistance is vital for optimization of its clinical utility. Additionally, there has been evidence that PARP inhibition may have a therapeutic role beyond HR deficient tumors which warrants further investigation, both as single agent and in combination with other therapeutic modalities like cytotoxic chemotherapy, radiation, targeted therapy and immunotherapy. With new strategies to overcome resistance and expand its therapeutic utility, PARP inhibitors are likely to become a staple in our armamentarium of drugs in cancer therapeutics.
Insights
Poly-(ADP-ribose) polymerase (PARP) inhibitors show promise in treating cancers with DNA repair defects, like ovarian cancer. Overcoming resistance and exploring new applications are key to maximizing the clinical utility of these important cancer therapeutics.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Poly-(ADP-ribose) polymerase (PARP) inhibitors exploit synthetic lethality in homologous recombination (HR) DNA repair-deficient cancers.
- PARP inhibitors are approved for ovarian cancer and show activity in other HR-deficient tumors like breast and prostate cancers.
- Several PARP inhibitors are FDA-approved, with others in late-stage development.
Purpose of the Study:
- To review the clinical utility of PARP inhibitors.
- To discuss challenges including primary and secondary resistance to PARP inhibition.
- To explore potential therapeutic roles beyond HR-deficient tumors and combination strategies.
Main Methods:
- Review of existing clinical data and research on PARP inhibitors.
- Analysis of mechanisms of action and resistance.
- Exploration of combination therapies and novel applications.
Main Results:
- PARP inhibitors are effective in HR-deficient cancers, with ongoing development of new agents.
- Resistance to PARP inhibitors presents a significant clinical challenge.
- Emerging evidence suggests PARP inhibition may benefit HR-proficient tumors and can be combined with other treatments.
Conclusions:
- Overcoming resistance and identifying predictive biomarkers are crucial for optimizing PARP inhibitor therapy.
- Expanding the therapeutic applications of PARP inhibitors, including combinations, holds significant promise for cancer treatment.
- PARP inhibitors are poised to become a cornerstone in cancer therapeutics.
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