{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Division of Cancer Biology, Research Institute, National Cancer Center, Goyang 10408, Republic of Korea.",
    "Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, Goyang 10408, Republic of Korea."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Hyeweon Jang",
      "orcid": "0000-0003-3841-018X"
    },
    {
      "affs": [
        0
      ],
      "name": "Hansol Jang",
      "orcid": "0000-0003-0028-6435"
    },
    {
      "affs": [
        0
      ],
      "name": "Hye Yeon Yun",
      "orcid": "0009-0002-1410-5041"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Kyung Yong Lee",
      "orcid": "0000-0003-2701-0762"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Hyonchol Jang",
      "orcid": "0000-0003-1436-457X"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/fmc3ppfehg6hk.bib",
  "cited_by": 0,
  "doi": "10.3390/ph19101538",
  "fulltext_url": "https://europepmc.org/articles/PMC13708644",
  "id": "fmc3ppfehg6hk",
  "issns": [
    "1424-8247"
  ],
  "landing_url": "https://europepmc.org/article/MED/42943235",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2730|PARP inhibition in cancer therapy"
    ]
  ],
  "openalex": "W7214601362",
  "pdf_url": "https://europepmc.org/articles/PMC13708644?pdf=render",
  "pmcid": "PMC13708644",
  "pmid": "42943235",
  "published": "2026-09-28",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/fmc3ppfehg6hk.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:22:24Z",
      "native_id": "MED:42943235",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42943235"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|PARP inhibition in cancer therapy",
      "subfield": "oncology"
    }
  ],
  "title": "Long-Term Drug Screening Identifies PARP Inhibitors as Irinotecan Combination Partners in BRCA1/2-Wild-Type Pancreatic Ductal Adenocarcinoma.",
  "title_text": "Long-Term Drug Screening Identifies PARP Inhibitors as Irinotecan Combination Partners in BRCA1/2-Wild-Type Pancreatic Ductal Adenocarcinoma.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:22:24Z",
  "url": "https://research.draconitic.com/paper/fmc3ppfehg6hk",
  "venue": "Pharmaceuticals (Basel, Switzerland)",
  "versions": []
}