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 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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
|---|---|
| Enthalten in: |
Cancers - 14(2022), 22 vom: 12. Nov. |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Smith, Hannah L [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
|---|
| Anmerkungen: |
Date Revised 13.12.2022 published: Electronic Citation Status PubMed-not-MEDLINE |
|---|
| doi: |
10.3390/cancers14225559 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM349416044 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM349416044 | ||
| 003 | DE-627 | ||
| 005 | 20231226042553.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.3390/cancers14225559 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1164.xml |
| 035 | |a (DE-627)NLM349416044 | ||
| 035 | |a (NLM)36428653 | ||
| 035 | |a (PII)5559 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Smith, Hannah L |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Differences in Durability of PARP Inhibition by Clinically Approved PARP Inhibitors |b Implications for Combinations and Scheduling |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 13.12.2022 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a ATR | |
| 650 | 4 | |a DDR | |
| 650 | 4 | |a PARP1 | |
| 650 | 4 | |a durability | |
| 700 | 1 | |a Willmore, Elaine |e verfasserin |4 aut | |
| 700 | 1 | |a Mukhopadhyay, Asima |e verfasserin |4 aut | |
| 700 | 1 | |a Drew, Yvette |e verfasserin |4 aut | |
| 700 | 1 | |a Curtin, Nicola J |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Cancers |d 2009 |g 14(2022), 22 vom: 12. Nov. |w (DE-627)NLM198667213 |x 2072-6694 |7 nnns |
| 773 | 1 | 8 | |g volume:14 |g year:2022 |g number:22 |g day:12 |g month:11 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.3390/cancers14225559 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 14 |j 2022 |e 22 |b 12 |c 11 | ||