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

Di Tano, M.; Ahmed, M.; Li, S.; Lyashenko, M.; Ruthen, N.; Tse, E.; Nathoo, I.; E. Echeverria, C.; Sanford, J.; Saleh, A.; Kim, J.; Dantas, E. C.; Pradella, D.; Rhee, K. Y. C.; Reznik, E.; Cantley, L. C.; Goncalves, M. D.

2026-09-29 cancer biology
10.64898/2026.09.29.754041 bioRxiv
Show 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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