Differences in durability of PARP inhibition by clinically approved PARP inhibitors: implications for combinations and scheduling
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 (PF50: 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..
| Medienart: |
|
|---|
Preprint| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
bioRxiv.org - (2022) vom: 28. Jan. Zur Gesamtaufnahme - year:2022 |
|---|
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Smith, Hannah L [VerfasserIn] |
|---|
| Links: |
Volltext [kostenfrei] |
|---|
| doi: |
10.1101/2022.01.24.477471 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
XBI035070897 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | XBI035070897 | ||
| 003 | DE-627 | ||
| 005 | 20230429074933.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 220126s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1101/2022.01.24.477471 |2 doi | |
| 035 | |a (DE-627)XBI035070897 | ||
| 035 | |a (biorXiv)10.1101/2022.01.24.477471 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 082 | 0 | |a 570 |q DE-84 | |
| 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: implications for combinations and scheduling |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a 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 (PF50: 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. | ||
| 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 bioRxiv.org |g (2022) vom: 28. Jan. |
| 773 | 1 | 8 | |g year:2022 |g day:28 |g month:01 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1101/2022.01.24.477471 |z kostenfrei |3 Volltext |
| 912 | |a GBV_XBI | ||
| 912 | |a SSG-OLC-PHA | ||
| 951 | |a AR | ||
| 952 | |j 2022 |b 28 |c 01 | ||
| 953 | |2 045F |a 570 | ||