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

Homologous recombination deficiency, commonly resulting from BRCA1/2 loss, is often accompanied by significant metabolic changes, though the full extent and potential treatments are still unclear. A comprehensive analysis of 10,619 tumors from The Cancer Genome Atlas (TCGA) and isogenic BRCA1/2-deficient models reveals that HRD tumors undergo widespread alterations in glucose metabolism.

Surprisingly, BRCA1/2 loss is linked to the upregulation of a specific, always active form of glycolytic enzyme Pyruvate Kinase M1 (PKM1), which is rare in most cancers and leads to increased pyruvate kinase activity. This unique glycolytic shift is achieved by activating PKM, a process that can be achieved using small molecules such as mitapivat, a drug already approved by the FDA.

The activation of PKM results in the accumulation of superoxide, disruption of PINK1-dependent mitochondrial quality control, DNA damage, and selective death of BRCA2-deficient tumors in living organisms, while leaving those with BRCA2 intact relatively unaffected. These discoveries shift the perspective on HRD from merely a metabolic state to a potentially modifiable target, suggesting that PKM activation could be a promising therapeutic approach for a specific subset of HR-deficient cancers.