CK2 in triple-negative breast cancer: oncogenic signaling networks and emerging CK2 inhibitor-based combination therapies.

Abstract

The aggressive and highly heterogeneous subtype of breast cancer, triple-negative breast cancer (TNBC), has a poor response to conventional treatments and a high propensity for metastasis, causing unfavorable clinical outcomes. In TNBC, casein kinase 2 (CK2), a constitutively active serine/threonine kinase, plays a key role in controlling several oncogenic signaling pathways. Aberrant CK2 signaling promotes increased transcription of oncogenes, proliferative signaling, DNA repair, epigenetic regulation, epithelial-to-mesenchymal transition (EMT), and cancer stem cell maintenance. Additionally, CK2 helps maintain tumor redox homeostasis by regulating the balance of zinc and copper and by stabilizing immunological checkpoint proteins such as PD-L1. Due to its pleiotropic effects, CK2 overactivation promotes treatment resistance across TNBC subtypes and accelerates tumor growth. Pharmacological inhibition of CK2 can disrupt these communication networks, making TNBC cells more susceptible to both traditional and targeted treatments. By concurrently suppressing compensatory survival mechanisms, CK2 inhibitors have demonstrated synergistic anticancer benefits when used with chemotherapy, PI3K/AKT/mTOR inhibitors, PARP inhibitors, and immunotherapies. This study highlights the complex role of aberrant CK2 signaling in TNBC progression and examines the therapeutic promise of CK2 inhibitor-based combination therapies to overcome resistance and improve treatment efficacy. Current preclinical and clinical research on next-generation CK2 inhibitors highlights their potential as a novel therapeutic approach for TNBC.