Differences in durability of PARP inhibition by clinically approved PARP inhibitors: implications for combinations and scheduling
Bibliographic record
Abstract
Abstract Five PARP inhibitors (PARPi) are approved for cancer treatment, they exploit cancer-specific defects in homologous recombination repair (HRR) to selectively kill tumour cells. Continuous PARP inhibition is required for single-agent anticancer activity. PARPi are also being investigated with ATR inhibitors clinically. We previously showed rucaparib caused prolonged PARP inhibition. Here we aimed to determine if this property was unique to rucaparib or common to other PARPis and the implications for scheduling with an ATR inhibitor (VE-821). Durability of PARP inhibition was determined at 0, 1, 24, 48 and 72 h after a 1 h pulse of 1μM of rucaparib, olaparib, niraparib, talazoparib or pamiparib in IGROV-1 (human ovarian cancer) cells. Inhibition of PARP was sustained to a variable degree with all inhibitors, but reduced with time. Rucaparib caused the most persistent inhibition of PARP activity, which was maintained at ≥75% for 72 h after drug withdrawal. In contrast, only 12% inhibition remained at this time with talazoparib and pamiparib and no detectable inhibition with olaparib and niraparib. Rucaparib enhanced VE-821 cytotoxicity to a similar extent in a sequential schedule as in co-exposure studies (PF 50 : 2.6 vs. 2.7) and there was even an approx. 2-fold enhancement after a 24 h delay between rucaparib and VE-821. Olaparib and niraparib produced similar enhancement of VE-821 cytotoxicity if co-exposed but were ineffective in sequential exposures. These data have clinical implications for both schedules of current PARPi monotherapy and the scheduling of PARPi in combination with ATRi and other cytotoxic drugs. Novelty and Impact PARPi are a new class of anticancer agent. We demonstrate for the first time that 5 PARPi continue to suppress cellular PARP activity after drug removal to a variable extent. Rucaparib caused the most durable PARP inhibition, olaparib and niraparib the least. Rucaparib enhanced ATR inhibitor cytotoxicity in sequential and co-exposures, olaparib and niraparib were only active in co-exposure settings. These data have implications for the clinical use of PARPi, particularly in combination with other drugs.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".