Work

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

Year: 2026

Type: preprint

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. Significance BRCA1/2-deficient cancers rely on an unusual PKM1-dominant glycolytic state. We show that pushing activity past a critical threshold by pharmacologically overactivating PKM triggers oxidative stress, disrupts mitochondrial quality control, and selectively kills BRCA2-deficient tumors. This reveals a druggable metabolic vulnerability in HRD cancers and repositions existing therapy for biomarker-guided treatment.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.09.29.754041