{
  "abstract": "Homologous recombination (HR) deficiency underlies a range of cancers, and PARP inhibitors (PARPi) targeting this vulnerability have demonstrated clinical efficacy in BRCA1/2-mutant tumors. However, resistance mechanisms and tolerability issues limit their long-term clinical effectiveness. Here, we characterize RP-3467, a novel, selective small-molecule inhibitor targeting the ATPase domain of DNA polymerase theta (Pol{theta}), the key mediator of the error-prone microhomology-mediated end joining (MMEJ) pathway. We demonstrate that RP-3467 potently suppresses Pol{theta} enzymatic activity, abrogates MMEJ, and disrupts mitotic DNA repair in HR-deficient (HRD) models, inducing synthetic lethality. In preclinical studies, we show that RP-3467 synergizes strongly with PARPi (olaparib and rucaparib), achieving sustained tumor regression across multiple xenograft and patient-derived xenograft (PDX) models without added systemic toxicity. Mechanistically, we find that RP-3467 increases mitotic DNA damage in vivo, as evidenced by elevated micronuclei and CIP2A foci. RP-3467 was evaluated in a phase 1 clinical trial (NCT06560632) and has shown preliminary signs of clinical activity. A heavily pretreated germline BRCA1-mutant ovarian cancer patient achieved a confirmed partial response to RP-3467 plus olaparib (RECIST v1.1), with retrospective profiling revealing a TP53BP1 loss-of-function mutation previously linked to both PARPi resistance and POLQ dependency. Although broader clinical validation is needed, these early findings suggest that Pol{theta} inhibition has the potential to address PARPi resistance and offer therapeutic benefit in HRD cancers.",
  "abstract_shown": true,
  "affiliations": [
    "Memorial Sloan Kettering Cancer Center"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 32,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "A. Sfeir"
    },
    {
      "name": "E. Rosen"
    },
    {
      "name": "M.-C. Mathieu"
    },
    {
      "name": "G. B. Ferraro"
    },
    {
      "name": "P. Mochirian"
    },
    {
      "name": "C. Godbout"
    },
    {
      "name": "H. Poirier"
    },
    {
      "name": "S. Fournier"
    },
    {
      "name": "D. A. Henry"
    },
    {
      "name": "H. Kim"
    },
    {
      "name": "R. Papp"
    },
    {
      "name": "S. Y. Yin"
    },
    {
      "name": "M.-E. Leclaire"
    },
    {
      "name": "R. Houle"
    },
    {
      "name": "P. Nejad"
    },
    {
      "name": "J. D. Schonhoft"
    },
    {
      "name": "K. Zahn"
    },
    {
      "name": "W. C. Black"
    },
    {
      "name": "M. Gallant"
    },
    {
      "name": "I. Kim"
    },
    {
      "name": "D. Ulanet"
    },
    {
      "name": "P. Basciano"
    },
    {
      "name": "A. Veloso"
    },
    {
      "name": "V. Rimkunas"
    },
    {
      "name": "T. A. Yap"
    },
    {
      "name": "R. Guo"
    },
    {
      "name": "N. Mai"
    },
    {
      "name": "M. Koehler"
    },
    {
      "name": "M. Zinda"
    },
    {
      "name": "A. Roulston"
    },
    {
      "name": "M. Zimmermann"
    },
    {
      "name": "S. J. Morris"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/bp8gx1h9n1vs9.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.16.26363059",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.09.16.26363059v1.full",
  "id": "bp8gx1h9n1vs9",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.09.16.26363059v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "oncology"
    ],
    [
      "openalex",
      "2730|PARP inhibition in cancer therapy"
    ]
  ],
  "openalex": "W7214044847",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.09.16.26363059v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-16",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/bp8gx1h9n1vs9.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:10Z",
      "native_id": "10.64898/2026.09.16.26363059",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.09.16.26363059v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:oncology",
      "subfield": "oncology"
    }
  ],
  "title": "Targeting Polθ Helicase with RP-3467: Preclinical Validation and Clinical Response in a gBRCA1 ovarian cancer patient with an acquired PARPi resistance mutation in TP53BP1",
  "title_text": "Targeting Polθ Helicase with RP-3467: Preclinical Validation and Clinical Response in a gBRCA1 ovarian cancer patient with an acquired PARPi resistance mutation in TP53BP1",
  "type": "preprint",
  "updated_at": "2026-10-30T12:19:10Z",
  "url": "https://research.draconitic.com/paper/bp8gx1h9n1vs9",
  "venue": "medRxiv",
  "versions": []
}