Long-Term Drug Screening Identifies PARP Inhibitors as Irinotecan Combination Partners in BRCA1/2-Wild-Type Pancreatic Ductal Adenocarcinoma.
- 1Division of Cancer Biology, Research Institute, National Cancer Center, Goyang 10408, Republic of Korea.
- 2Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, Goyang 10408, Republic of Korea.
Abstract
Background/Objectives: Irinotecan is a component of standard first-line regimens for advanced pancreatic ductal adenocarcinoma (PDAC), yet cells that survive irinotecan treatment may retain the capacity to re-establish growth. Most anticancer drug screens use short-term growth inhibition as an initial criterion for compound selection, potentially excluding compounds with limited acute activity. We asked whether some of these excluded candidates might nevertheless show substantial long-term activity and enhance irinotecan responses in combination. Methods: We first screened 3524 compounds for short-term growth inhibition and advanced compounds with limited acute activity to a 10-day colony-growth screen. Long-term hits were narrowed to clinically relevant anticancer agents and then screened with irinotecan. Talazoparib showed the lowest combination-to-single-agent score and was selected for further evaluation. The combination was evaluated across multiple BRCA1/2-wild-type PDAC cell lines and further validated using additional PARP inhibitors and a xenograft model. RNA sequencing and γH2AX analysis were used to examine associated DNA damage-response features. Results: Of the 1877 compounds advanced from the initial 3-day screen, 334 (17.8%) met the long-term hit criterion. In short- versus long-term comparisons, irinotecan plus talazoparib produced greater growth suppression and higher Bliss synergy scores in 10-day than in 72 h assays. Enhanced long-term responses were observed across five BRCA1/2-wild-type PDAC cell lines, and similar long-term effects were observed with three additional PARP inhibitors. The combination also showed synergistic antitumor activity in an MIA PaCa-2 subcutaneous xenograft model. Transcriptomic and γH2AX analyses provided findings consistent with replication-stress and DNA-damage-response processes. Conclusions: A substantial subset of compounds with limited acute activity showed substantial long-term activity. PARP inhibition enhanced irinotecan responses and emerged as a candidate combination strategy in BRCA1/2-wild-type PDAC.
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BibTeX
@article{jang2026longterm,
title = {{Long-Term Drug Screening Identifies PARP Inhibitors as Irinotecan Combination Partners in BRCA1/2-Wild-Type Pancreatic Ductal Adenocarcinoma.}},
author = {Hyeweon Jang and Hansol Jang and Hye Yeon Yun and Kyung Yong Lee and Hyonchol Jang},
journal = {Pharmaceuticals (Basel, Switzerland)},
year = {2026},
month = sep,
doi = {10.3390/ph19101538},
url = {https://europepmc.org/article/MED/42943235},
note = {CC BY},
}
RIS
TY - JOUR
TI - Long-Term Drug Screening Identifies PARP Inhibitors as Irinotecan Combination Partners in BRCA1/2-Wild-Type Pancreatic Ductal Adenocarcinoma.
AU - Hyeweon Jang
AU - Hansol Jang
AU - Hye Yeon Yun
AU - Kyung Yong Lee
AU - Hyonchol Jang
PY - 2026
DA - 2026/09/28
JO - Pharmaceuticals (Basel, Switzerland)
DO - 10.3390/ph19101538
UR - https://europepmc.org/article/MED/42943235
AB - Background/Objectives: Irinotecan is a component of standard first-line regimens for advanced pancreatic ductal adenocarcinoma (PDAC), yet cells that survive irinotecan treatment may retain the capacity to re-establish growth. Most anticancer drug screens use short-term growth inhibition as an initial criterion for compound selection, potentially excluding compounds with limited acute activity. We asked whether some of these excluded candidates might nevertheless show substantial long-term activity and enhance irinotecan responses in combination. Methods: We first screened 3524 compounds for short-term growth inhibition and advanced compounds with limited acute activity to a 10-day colony-growth screen. Long-term hits were narrowed to clinically relevant anticancer agents and then screened with irinotecan. Talazoparib showed the lowest combination-to-single-agent score and was selected for further evaluation. The combination was evaluated across multiple BRCA1/2-wild-type PDAC cell lines and further validated using additional PARP inhibitors and a xenograft model. RNA sequencing and γH2AX analysis were used to examine associated DNA damage-response features. Results: Of the 1877 compounds advanced from the initial 3-day screen, 334 (17.8%) met the long-term hit criterion. In short- versus long-term comparisons, irinotecan plus talazoparib produced greater growth suppression and higher Bliss synergy scores in 10-day than in 72 h assays. Enhanced long-term responses were observed across five BRCA1/2-wild-type PDAC cell lines, and similar long-term effects were observed with three additional PARP inhibitors. The combination also showed synergistic antitumor activity in an MIA PaCa-2 subcutaneous xenograft model. Transcriptomic and γH2AX analyses provided findings consistent with replication-stress and DNA-damage-response processes. Conclusions: A substantial subset of compounds with limited acute activity showed substantial long-term activity. PARP inhibition enhanced irinotecan responses and emerged as a candidate combination strategy in BRCA1/2-wild-type PDAC.
SN - 1424-8247
ER -