Differences in Durability of PARP Inhibition by Clinically Approved PARP Inhibitors: Implications for Combinations and Scheduling

Six PARP inhibitors (PARPi) are approved for cancer therapy as monotherapy agents in daily or twice-daily continuous dosing schedules to maintain the necessary continuous suppression of PARP activity. Continuous PARP inhibition is required for single-agent anticancer activity. To investigate if such...

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Published inCancers Vol. 14; no. 22; p. 5559
Main Authors Smith, Hannah L, Willmore, Elaine, Mukhopadhyay, Asima, Drew, Yvette, Curtin, Nicola J
Format Journal Article
LanguageEnglish
Published Switzerland MDPI AG 12.11.2022
MDPI
Subjects
Antitumor activity
Cancer
Care and treatment
Cell cycle
Clinical trials
Cytotoxicity
DNA damage
Dosage and administration
Enzyme inhibitors
Ovarian cancer
Poly(ADP-ribose) polymerase
Proteins
Scheduling
Software
United Kingdom
United Kingdom > UK
United States > US
DDR
PARP1
durability
ATR
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Summary:Six PARP inhibitors (PARPi) are approved for cancer therapy as monotherapy agents in daily or twice-daily continuous dosing schedules to maintain the necessary continuous suppression of PARP activity. Continuous PARP inhibition is required for single-agent anticancer activity. To investigate if such intense schedules are necessary, we determined the durability of PARP inhibition up to 72 h after a 1 h pulse of 1 µM of five of the approved PARPi, rucaparib, olaparib, niraparib, talazoparib and pamiparib, in IGROV-1 and ES-2 (human ovarian cancer) cells. Rucaparib caused the most persistent inhibition of PARP activity when maintained at ≥75% at 72 h after drug withdrawal in both IGROV-1 and ES-2 cells, but inhibition was more rapidly lost with the other PARPi. PARPi are also under clinical investigation with ATR inhibitors, and thus, we evaluated the implications for scheduling with an ATR inhibitor (VE-821). Rucaparib enhanced VE-821 cytotoxicity in co-exposure, sequential and delayed (24 h drug-free) schedules in IGROV-1 and ES-2 cells. Olaparib and niraparib enhanced VE-821 cytotoxicity only in co-exposed cells and not in sequential exposures. These data have clinical implications for the scheduling of PARPi as a monotherapy and in combination with ATR inhibitors and other cytotoxic drugs.
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ISSN:2072-6694
2072-6694
DOI:10.3390/cancers14225559