{
  "abstract": "Homologous recombination deficiency (HRD), most commonly arising from BRCA1/2 loss, is accompanied by metabolic remodeling whose contours and therapeutic implications remain poorly defined. Through pan-cancer analysis of 10,619 tumors from The Cancer Genome Atlas (TCGA) and isogenic BRCA1/2-deficient models, we show that HRD tumors display broad metabolic rewiring, with consistent alterations in glucose metabolism. Unexpectedly, BRCA1/2 loss is associated with selective upregulation of the constitutively active glycolytic enzyme Pyruvate Kinase M1 (PKM1) isoform, contrasting with the PKM2-dominant state of most cancers, and produces an elevated pyruvate kinase activity state. Overactivating PKM, with small molecules activators, including the FDA-approved drug mitapivat, triggers superoxide accumulation, disrupts PINK1-dependent mitochondrial quality control, induces DNA damage, and selectively kills BRCA2-deficient tumors in vivo, while sparing BRCA2-proficient counterparts. These findings recast HRD as a metabolic state and identify PKM activation as a candidate therapeutic strategy for biomarker-selected HR-deficient cancers.",
  "abstract_shown": true,
  "affiliations": [
    "NYU Grossman School of Medicine"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 17,
  "authors": [
    {
      "name": "M. Di Tano"
    },
    {
      "name": "M. Ahmed"
    },
    {
      "name": "S. Li"
    },
    {
      "name": "M. Lyashenko"
    },
    {
      "name": "N. Ruthen"
    },
    {
      "name": "E. Tse"
    },
    {
      "name": "I. Nathoo"
    },
    {
      "name": "C. E. Echeverria"
    },
    {
      "name": "J. Sanford"
    },
    {
      "name": "A. Saleh"
    },
    {
      "name": "J. Kim"
    },
    {
      "name": "E. C. Dantas"
    },
    {
      "name": "D. Pradella"
    },
    {
      "name": "K. Y. C. Rhee"
    },
    {
      "name": "E. Reznik"
    },
    {
      "name": "L. C. Cantley"
    },
    {
      "affs": [
        0
      ],
      "name": "M. D. Goncalves"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/55wkbkejhpxtm.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.29.754041",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.29.754041v1.full",
  "id": "55wkbkejhpxtm",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.29.754041v1",
  "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",
      "1306|Cancer, Hypoxia, and Metabolism"
    ]
  ],
  "openalex": "W7214701816",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.29.754041v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-29",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/55wkbkejhpxtm.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:25:11Z",
      "native_id": "10.64898/2026.09.29.754041",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.29.754041v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:cancer biology",
      "subfield": "oncology"
    }
  ],
  "title": "BRCA2 loss drives a PKM1-dominant glycolytic state that is selectively lethal to pyruvate kinase activation",
  "title_text": "BRCA2 loss drives a PKM1-dominant glycolytic state that is selectively lethal to pyruvate kinase activation",
  "type": "preprint",
  "updated_at": "2026-10-30T12:25:11Z",
  "url": "https://research.draconitic.com/paper/55wkbkejhpxtm",
  "venue": "bioRxiv",
  "versions": []
}