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Targeting Pyruvate Kinase M2 phosphorylation reverses aggressive cancer phenotypes

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with low survival rate and a lack of biomarkers and targeted treatments. Here we target pyruvate kinase M2 (PKM2), a key metabolic component of oncogenesis. In TNBC patients, PKM2pS37 was identified as a prominent phosphoprotein corresponding to the aggressive breast cancer phenotype that showed a characteristic nuclear staining pattern and prognostic value. Phosphorylation of PKM2 at S37 was connected with a cyclin-dependent kinase (CDK) pathway in TNBC cells. In parallel, pyruvate kinase activator TEPP-46 bound PKM2pS37 and reduced its nuclear localization. In a TNBC mouse xenograft model, treatment with either TEPP-46 or the potent CDK inhibitor Dinaciclib reduced tumor growth and diminished PKM2pS37. Combinations of Dinaciclib with TEPP-46 reduced cell invasion, impaired redox balance, and triggered cancer cell death. Collectively, these data support an approach to identify PKM2pS37-positive TNBC and target the PKM2 regulatory axis as a potential treatment.

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Cat.No. Product Name Information
S2768 Dinaciclib Dinaciclib is a novel and potent CDK inhibitor for CDK2, CDK5, CDK1 and CDK9 with IC50 of 1 nM, 1 nM, 3 nM and 4 nM in cell-free assays, respectively. It also blocks thymidine (dThd) DNA incorporation. Dinaciclib induces apoptosis through the activation of caspases 8 and 9. Phase 3.

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Caspase CDK