BRCA2 loss drives a PKM1-dominant glycolytic state that is selectively lethal to pyruvate kinase activation

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.

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BibTeX RIS

BibTeX

@misc{tano2026brca2,
  title = {{BRCA2 loss drives a PKM1-dominant glycolytic state that is selectively lethal to pyruvate kinase activation}},
  author = {M. Di Tano and M. Ahmed and S. Li and M. Lyashenko and N. Ruthen and E. Tse and I. Nathoo and C. E. Echeverria and J. Sanford and A. Saleh and J. Kim and E. C. Dantas and D. Pradella and K. Y. C. Rhee and E. Reznik and L. C. Cantley and M. D. Goncalves},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.29.754041},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.29.754041v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - BRCA2 loss drives a PKM1-dominant glycolytic state that is selectively lethal to pyruvate kinase activation
AU  - M. Di Tano
AU  - M. Ahmed
AU  - S. Li
AU  - M. Lyashenko
AU  - N. Ruthen
AU  - E. Tse
AU  - I. Nathoo
AU  - C. E. Echeverria
AU  - J. Sanford
AU  - A. Saleh
AU  - J. Kim
AU  - E. C. Dantas
AU  - D. Pradella
AU  - K. Y. C. Rhee
AU  - E. Reznik
AU  - L. C. Cantley
AU  - M. D. Goncalves
PY  - 2026
DA  - 2026/09/29
PB  - bioRxiv
DO  - 10.64898/2026.09.29.754041
UR  - https://www.biorxiv.org/content/10.64898/2026.09.29.754041v1
AB  - 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.
ER  -

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