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PARP inhibition in cancer therapy
Research Guide
What is PARP inhibition in cancer therapy?
PARP inhibition in cancer therapy is the use of Poly(ADP-ribose) Polymerase (PARP) inhibitors, such as Olaparib and Niraparib, to target DNA repair deficiencies in cancer cells, particularly those with BRCA1/2 mutations, exploiting synthetic lethality to induce cell death.
PARP inhibitors block PARP enzymes involved in DNA single-strand break repair, leading to replication fork collapse and cell death in homologous recombination-deficient cancers. The field encompasses 36,336 papers focused on synthetic lethality in BRCA mutant cells and applications in platinum-sensitive ovarian cancer. Key examples include Olaparib demonstrating antitumor activity in BRCA mutation carriers.
Topic Hierarchy
Research Sub-Topics
PARP Inhibitors in BRCA-Mutant Cancers
This sub-topic examines the efficacy of Olaparib, Niraparib, and other PARP inhibitors in BRCA1/2-mutated ovarian, breast, and prostate cancers through clinical trials and resistance mechanisms. Researchers study biomarker-driven patient selection and combination therapies.
Synthetic Lethality in DNA Repair
This sub-topic covers genetic interaction screens identifying synthetic lethal partners beyond BRCA, including HRD signatures and alternative repair pathways. Researchers develop CRISPR-based screens and computational models for novel drug targets.
Homologous Recombination Deficiency
This sub-topic focuses on HRD detection via genomic scarring, RAD51 foci assays, and functional assays for therapy response prediction. Researchers correlate HRD scores with PARP inhibitor sensitivity across solid tumors.
PARP Inhibitor Resistance Mechanisms
This sub-topic investigates reversion mutations, drug efflux pumps, and alternative DNA repair pathway reactivation conferring resistance. Researchers explore combination strategies with ATR/CHK1 inhibitors and novel PARPi generations.
PARP Trapping and DNA Damage
This sub-topic elucidates PARP-DNA trapping as the primary cytotoxic mechanism, distinct from catalytic inhibition, and its replication fork protection role. Researchers study structure-activity relationships and off-target effects of clinical PARPi.
Why It Matters
PARP inhibitors provide targeted therapy for cancers with BRCA1/2 mutations, offering benefits over conventional chemotherapy with fewer adverse effects. Fong et al. (2009) in "Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers" showed Olaparib inhibits PARP and exhibits antitumor activity in BRCA-associated cancers (ClinicalTrials.gov NCT00516373). Robson et al. (2017) in "Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation" reported olaparib monotherapy extended median progression-free survival by 2.8 months and reduced the risk of disease progression or death by 42% in HER2-negative metastatic breast cancer patients with germline BRCA mutations compared to standard therapy.
Reading Guide
Where to Start
"Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy" by Farmer et al. (2005) introduces the foundational concept of synthetic lethality with PARP inhibitors in BRCA mutant cells, making it the ideal starting point for understanding the mechanism.
Key Papers Explained
Farmer et al. (2005) in "Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy" first proposed PARP inhibition as a strategy exploiting BRCA defects, with 6496 citations. Bryant et al. (2005) in "Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase" (5038 citations) validated selective tumor killing in BRCA2-deficient models. Fong et al. (2009) in "Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers" (3582 citations) provided clinical proof-of-concept with Olaparib in patients. Robson et al. (2017) in "Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation" (3056 citations) extended evidence to breast cancer with progression-free survival data.
Paper Timeline
Most-cited paper highlighted in red. Papers ordered chronologically.
Advanced Directions
Clinical applications dominate with trials like NCT00516373 for Olaparib in BRCA cancers, but no recent preprints detail new frontiers. Focus remains on BRCA1/2 deficiencies and synthetic lethality as explored in top-cited works.
Papers at a Glance
| # | Paper | Year | Venue | Citations | Open Access |
|---|---|---|---|---|---|
| 1 | Targeting the DNA repair defect in BRCA mutant cells as a ther... | 2005 | Nature | 6.5K | ✕ |
| 2 | Dose translation from animal to human studies revisited | 2007 | The FASEB Journal | 6.1K | ✕ |
| 3 | Specific killing of BRCA2-deficient tumours with inhibitors of... | 2005 | Nature | 5.0K | ✕ |
| 4 | Identification and inhibition of the ICE/CED-3 protease necess... | 1995 | Nature | 4.0K | ✕ |
| 5 | Anthracyclines: Molecular Advances and Pharmacologic Developme... | 2004 | Pharmacological Reviews | 3.7K | ✕ |
| 6 | Bid, a Bcl2 Interacting Protein, Mediates Cytochrome c Release... | 1998 | Cell | 3.6K | ✓ |
| 7 | Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from <i>BR... | 2009 | New England Journal of... | 3.6K | ✓ |
| 8 | Olaparib for Metastatic Breast Cancer in Patients with a Germl... | 2017 | New England Journal of... | 3.1K | ✓ |
| 9 | Triple-negative breast cancer: challenges and opportunities of... | 2016 | Nature Reviews Clinica... | 2.9K | ✓ |
| 10 | Cell-cycle checkpoints and cancer | 2004 | Nature | 2.8K | ✕ |
Frequently Asked Questions
What is synthetic lethality in PARP inhibition?
Synthetic lethality occurs when PARP inhibition combined with BRCA deficiency causes cell death due to unrepaired DNA damage. Farmer et al. (2005) in "Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy" demonstrated this by showing PARP inhibitors selectively kill BRCA mutant cells. Bryant et al. (2005) in "Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase" confirmed PARP inhibitors kill BRCA2-deficient tumors through this mechanism.
How do PARP inhibitors work in BRCA mutant cancers?
PARP inhibitors trap PARP on DNA, preventing repair and causing double-strand breaks that homologous recombination-deficient cells cannot fix. Farmer et al. (2005) targeted the DNA repair defect in BRCA mutant cells with this strategy. Fong et al. (2009) showed Olaparib inhibits PARP in BRCA mutation carrier tumors.
What clinical evidence supports Olaparib in cancer therapy?
Olaparib monotherapy benefits BRCA-mutated cancers with improved progression-free survival. Robson et al. (2017) reported a 2.8-month longer median progression-free survival in germline BRCA-mutated, HER2-negative metastatic breast cancer. Fong et al. (2009) observed antitumor activity with few adverse effects in BRCA-associated cancers.
Which cancers benefit from PARP inhibitors?
PARP inhibitors target BRCA1/2-deficient cancers including ovarian, breast, and platinum-sensitive ovarian cancer. Fong et al. (2009) showed activity in BRCA mutation carriers. Robson et al. (2017) confirmed efficacy in metastatic breast cancer with germline BRCA mutations.
What is the role of homologous recombination in PARP inhibition?
Homologous recombination deficiency sensitizes cells to PARP inhibitors due to inability to repair double-strand breaks. Farmer et al. (2005) and Bryant et al. (2005) established this through selective killing of BRCA mutant cells. The mechanism relies on synthetic lethality between PARP and BRCA pathways.
Open Research Questions
- ? How can resistance to PARP inhibitors in BRCA-mutated cancers be overcome?
- ? What biomarkers beyond BRCA1/2 predict response to PARP inhibitors?
- ? Can PARP inhibitors be combined with other DNA repair-targeted therapies without excessive toxicity?
- ? How do PARP trapping versus catalytic inhibition mechanisms differ in clinical efficacy?
- ? What is the long-term impact of PARP inhibitors on patient survival in non-BRCA deficient cancers?
Recent Trends
The field includes 36,336 papers with no specified 5-year growth rate.
High-impact clinical papers like Robson et al. on Olaparib in breast cancer (3056 citations) represent established trends, with no recent preprints or news indicating shifts.
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