{
  "abstract": "Patients with TP53-mutant myelodysplasic syndromes (MDS) and acute myeloid leukemia (AML) are usually elderly and frail with highly resistant malignant clones and a median survival of less than one year. The molecule APR-246 targets mutant p53 but also perturbs redox homeostasis. APR-246 showed favorable safety in a phase 3 trial in TP53 mutant MDS/AML but did not meet efficacy endpoints in combination with azacitidine (AZA), highlighting the need for more effective combination strategies. Conversion of APR-246 to the active compound MQ releases formaldehyde which generates DNA-protein crosslinks. AML cells depend on DNA polymerase theta (Pol[O]) to repair such lesions and Pol[O] protects cells from ferroptosis. Using a panel of isogenic MOLM13 AML cell lines each carrying a common TP53 variant, we show that the Pol[O] inhibitor Novobiocin (NVB) synergizes with APR-246 to induce AML cell death. We demonstrate strong synergy with this combination in all TP53 mutant cell lines and to a lesser extent in the TP53 wildtype and null cells, indicating both p53-dependent and p53-independent mechanisms behind the synergy. APR-246 provides selectivity for TP53-mutated cells while NVB enhances p53-independent apoptosis and p53-dependent ferroptosis. Levels of ferroptosis induction correlate with the observed synergy in TP53-mutant and WT cells. Combination of APR-246 and NVB induces potent in vitro growth inhibition of primary TP53-mutated AML/CMML patient samples, with significant activity achieved at low micromolar or nanomolar concentrations of APR-246. Our findings hold promise for combination of APR-246 and NVB as a new therapeutic strategy tailored for TP53-mutated AML patients with high efficacy and low toxicity.",
  "abstract_shown": true,
  "affiliations": [
    "Karolinska Institutet"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "name": "A. Tuval"
    },
    {
      "name": "T. Lasho"
    },
    {
      "name": "A. Spada"
    },
    {
      "name": "M. M. Patnaik"
    },
    {
      "affs": [
        0
      ],
      "name": "K. G. Wiman"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/b6ryyk78ga92q.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.30.763043",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.30.763043v1.full",
  "id": "b6ryyk78ga92q",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.30.763043v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "cancer biology"
    ]
  ],
  "openalex": null,
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.30.763043v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-30",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/b6ryyk78ga92q.ris",
  "sources": [
    {
      "first_seen": "2026-11-03T00:20:41Z",
      "native_id": "10.64898/2026.10.30.763043",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.30.763043v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:cancer biology",
      "subfield": "oncology"
    }
  ],
  "title": "APR-246 and DNA polymerase theta inhibitor Novobiocinsynergize to eliminate TP53 mutant AML cells",
  "title_text": "APR-246 and DNA polymerase theta inhibitor Novobiocinsynergize to eliminate TP53 mutant AML cells",
  "type": "preprint",
  "updated_at": "2026-11-04T00:21:13Z",
  "url": "https://research.draconitic.com/paper/b6ryyk78ga92q",
  "venue": "bioRxiv",
  "versions": []
}