Abstract 6808: Targeting metabolism in BRCA-deficient tumors

Abstract Up to 10% of all cancers are attributed to genetic predisposition, with inherited mutations in BRCA1 and BRCA2 being the most significant risk factors for developing breast and ovarian cancers. These mutations also increase susceptibility to other malignancies, including prostate, pancreatic, and colorectal cancers. The BRCA1 and BRCA2 proteins play essential roles in homologous recombination (HR), an error-free DNA repair process. When cells lack functional BRCA1 or BRCA2, they become reliant on alternative, error-prone DNA repair mechanisms, which drive genomic instability and tumorigenesis. Although Poly (ADP-ribose) polymerase (PARP) inhibitors have revolutionized targeted therapy for tumors with BRCA1/2 mutations, the emergence of resistance limits their long-term efficacy, highlighting the urgent need for novel therapeutic strategies. Cancer metabolism of BRCA1/2-deficient tumors remains largely uncharacterized and poorly understood.To address this gap, we analyzed 10,619 tumors representing 33 cancer types using data from The Cancer Genome Atlas (TCGA). Our findings revealed that tumors with HR deficiency signatures exhibit distinct metabolic profiles compared to HR-proficient tumors. Further validation in BRCA2-/- cancer cell models confirmed that BRCA2-deficient tumor cells rely heavily on the activity of pyruvate kinase (PK), an enzyme that catalyzes the final step of glycolysis. Pyruvate kinase exists as two splice isoforms: PKM1, which is constitutively active, and PKM2, which is allosterically regulated. Most cancer cells predominantly express PKM2, as its low activity state enables metabolic flexibility by redirecting glucose-derived carbons from energy production to biosynthesis for growth and survival. Remarkably, we showed for the first time that BRCA1/2-deficient tumor cells and mouse-derived tumors, not only express PKM2, but also the constitutively active PKM1. Therefore, we targeted PKM, and we found that PKM activators selectively kill BRCA2-deficient cancer cells, but not BRCA2-proficient ones, by inducing DNA damage, reducing lactate production, and decreasing glucose oxidation. Notably, PKM1 overexpression in BRCA2-proficient cells phenocopies the sensitivity of BRCA2-deficient cells to PKM activators, suggesting that PKM1 mediates, at least in part, this effect. Our results also reveal that the toxic impact of PKM activators in BRCA2-deficient cancer cells involves impaired mitophagy and mitochondrial dysfunction. Together, these findings provide a strong rationale for targeting pyruvate kinase in BRCA1/2 deficient and potentially other HR-deficient tumor subtypes. Citation Format: Maira Di Tano, Mujmmail Ahmed, Li Shiri, Michael Lyashenko, Neil Ruthen, Ethan Tse, Davide Pradella, Carolina Echeverria-Andrade, Isaac Nathoo, Jack Sanford, Ezequiel Dantas, Jeshua Kim, Anas Saleh, Rhee Kyu, Ed Reznik, Lewis C. Cantley, Marcus DaSilva Goncalves. Targeting metabolism in BRCA-deficient tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6808.