6-[(3-aminophenyl)methyl]-4-methyl-2-methylsulfinyl-5-thieno[3-4]pyrrolo[1-3-d]pyridazinone and dinaciclib

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 patients with TNBC, 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. SIGNIFICANCE: PKM2 phosphorylation marks aggressive breast cancer cell phenotypes and targeting PKM2pS37 could be an effective therapeutic approach for treating triple-negative breast cancer.

Topics: Active Transport, Cell Nucleus; Animals; Biomarkers, Tumor; Carrier Proteins; Cell Line, Tumor; Collagen; Cyclic N-Oxides; Drug Combinations; Genome, Human; Humans; Indolizines; Laminin; MCF-7 Cells; Membrane Proteins; Mice; Neoplasm Invasiveness; Neoplasm Transplantation; Neoplasms; Oxidation-Reduction; Phenotype; Phosphorylation; Protein Isoforms; Proteoglycans; Proteomics; Pyridazines; Pyridinium Compounds; Pyrroles; Pyruvate Kinase; Thyroid Hormone-Binding Proteins; Thyroid Hormones; Triple Negative Breast Neoplasms