{
  "abstract": "The B-cell lymphoma 2 inhibitor venetoclax has therapeutic activity in several hematological malignancies. In acute myeloid leukemia (AML), venetoclax combined with hypomethylating agents is the standard of care for patients unfit for intensive chemotherapy, but intrinsic and acquired resistance are common. Loss of p53 function is strongly associated with venetoclax resistance, and adding venetoclax to 5-azacitidine provides no overall survival benefit in TP53-mutant AML. Other frequent mechanisms of venetoclax resistance in AML include FLT3 mutations, myeloid cell leukemia 1 (MCL-1) upregulation, and altered mitochondrial metabolism. However, it has been challenging to develop agents that target these mechanisms directly and combinatorially. Here, we report that pitavastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, promotes apoptosis and overcomes several venetoclax resistance mechanisms in human AML cells. At clinically achievable concentrations, pitavastatin treatment has potent cytotoxic activity in cells with mutations in TP53 or FLT3, including primary cells resistant to venetoclax and 5-azacitidine. The apoptotic mechanism involves p53-independent PUMA upregulation and reduced MCL-1 expression. Pitavastatin also suppresses mitochondrial gene expression, oxidative metabolism, and MYC/E2F-driven transcription. These results provide a mechanistic rationale for clinical trials adding pitavastatin to AML regimens to prevent or overcome venetoclax resistance with TP53 mutations and other high-risk features.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Molecular Biology & Biochemistry, University of California Irvine, Irvine, CA.",
    "The Ohio State University Wexner Medical Center, Columbus, OH.",
    "Division of Hematology & Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA.",
    "Division of Hematology & Oncology, College of Medicine, University of Cincinnati, Cincinnati, OH.",
    "Department of Biological Chemistry, Center for Epigenetics and Metabolism, University of California Irvine, Irvine, CA.",
    "Department of Chemistry, University of California Irvine, Irvine, CA.",
    "Biostatistics Shared Resource, University of California Irvine Chao Family Comprehensive Cancer Center, Orange, CA.",
    "Department of Epidemiology and Biostatistics, University of California Irvine, Irvine, CA.",
    "Department of Pathology & Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA.",
    "Hematology/Oncology Section, VA Long Beach Healthcare System, Long Beach, CA.",
    "Division of Hematology-Oncology, Department of Medicine, University of California Irvine, Irvine, CA.",
    "Department of Pharmacology and Toxicology and Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA.",
    "Albert Einstein College of Medicine, Montefiore Einstein Comprehensive Cancer Center, Bronx, NY."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 21,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Roberta Buono"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Dennis Juarez"
    },
    {
      "affs": [
        0
      ],
      "name": "Madhuri Paul"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Sarah J Skuli"
    },
    {
      "affs": [
        0
      ],
      "name": "Ian B Wong"
    },
    {
      "affs": [
        0
      ],
      "name": "Ishita Tarnekar"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhili Ying"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Izabelle Marie F Le"
    },
    {
      "affs": [
        6
      ],
      "name": "Wen-Pin Chen"
    },
    {
      "affs": [
        6,
        7
      ],
      "name": "Min Zhang"
    },
    {
      "affs": [
        2,
        8
      ],
      "name": "Gerald Wertheim"
    },
    {
      "affs": [
        2
      ],
      "name": "A'ishah Bakayoko"
    },
    {
      "affs": [
        2
      ],
      "name": "Marisa Kruidenier"
    },
    {
      "affs": [
        0
      ],
      "name": "Dequina A Nicholas"
    },
    {
      "affs": [
        9,
        10
      ],
      "name": "Pankaj Gupta"
    },
    {
      "affs": [
        11
      ],
      "name": "Said M Sebti"
    },
    {
      "affs": [
        12
      ],
      "name": "Marina Konopleva"
    },
    {
      "affs": [
        10
      ],
      "name": "Angela G Fleischman"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Cholsoon Jang"
    },
    {
      "affs": [
        2
      ],
      "name": "Martin Carroll"
    },
    {
      "affs": [
        0
      ],
      "name": "David A Fruman"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/937r151z8rtzd.bib",
  "cited_by": 0,
  "doi": "10.1016/j.bneo.2026.100296",
  "fulltext_url": "https://europepmc.org/articles/PMC13676112",
  "id": "937r151z8rtzd",
  "issns": [
    "2950-3280"
  ],
  "landing_url": "https://europepmc.org/article/MED/42893198",
  "language": "eng",
  "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": [
    [
      "openalex",
      "2720|Acute Myeloid Leukemia Research"
    ]
  ],
  "openalex": "W7204530725",
  "pdf_url": "https://europepmc.org/articles/PMC13676112?pdf=render",
  "pmcid": "PMC13676112",
  "pmid": "42893198",
  "published": "2026-08-28",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/937r151z8rtzd.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:18Z",
      "native_id": "MED:42893198",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42893198"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2720|Acute Myeloid Leukemia Research",
      "subfield": "general"
    }
  ],
  "title": "Pitavastatin counteracts venetoclax resistance mechanisms including TP53 mutation in acute myeloid leukemia.",
  "title_text": "Pitavastatin counteracts venetoclax resistance mechanisms including TP53 mutation in acute myeloid leukemia.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:18Z",
  "url": "https://research.draconitic.com/paper/937r151z8rtzd",
  "venue": "Blood neoplasia",
  "versions": []
}