NIMA-related Kinase 2: A master regulator of mitotic fidelity and chromosomal instability in cancer: From mechanisms to therapeutic targeting.

NEK2 (NIMA-Related Kinase 2), a serine/threonine kinase, is a pivotal kinase for centrosome separation and mitotic fidelity. It is increasingly recognized as a driver of oncogenesis and a contributor to therapeutic resistance. This review comprehensively discusses the structural features, expression patterns, and multilayered regulation of NEK2, along with its interactions with signaling molecules, its function, and an in-depth investigation of its roles in various diseases, specifically different types of cancers. It further highlights NEK2's involvement in signaling pathways, its contribution to chromosomal instability and tumor progression, and its potential as both a biomarker and therapeutic target in cancer. Dysregulated NEK2 causes chromosomal instability, metastatic progression, and immune evasion across diverse cancers by disrupting centrosome dynamics, rewiring oncogenic pathways (e.g., PI3K-AKT, Wnt/β-catenin), and inactivating tumor suppressors such as p53. Overexpression of NEK2 correlates with poor prognosis and chemoresistance in haematological and solid tumors, suggesting its role as a biomarker and therapeutic target. Apart from its role in cancer, dysfunction of NEK2 contributes to polycystic kidney disease, bone remodeling, and immune dysregulation, highlighting its pleiotropic roles. Recent advances in targeting NEK2 include covalent inhibitors (e.g., JH295), Hec1 disruptors (e.g.,  INH154), and clinical-stage compounds (e.g., T-1101), alongside emerging strategies such as PROTACs and immunotherapy. However, challenges remain in developing selective, clinically viable agents. This review provides details on the molecular architecture of NEK2, disease mechanisms, and therapeutic potential, framing it as a dual regulator and guardian of mitosis that has become a rogue oncogene and advocating its exploitation in translational medicine across cancer and non-cancer pathologies.